U.S. patent number 8,268,843 [Application Number 12/550,952] was granted by the patent office on 2012-09-18 for 5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines and their use as agrochemicals.
This patent grant is currently assigned to Dow AgroSciences, LLC.. Invention is credited to William K. Brewster, Carla J. R. Klittich, Brent J. Rieder, Chenglin Yao, Yuanming Zhu.
United States Patent |
8,268,843 |
Brewster , et al. |
September 18, 2012 |
5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines
and their use as agrochemicals
Abstract
The present disclosure relates to
5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines
and their use as agrochemicals and animal health products.
Inventors: |
Brewster; William K.
(Indianapolis, IN), Klittich; Carla J. R. (Zionsville,
IN), Yao; Chenglin (Westfield, IN), Zhu; Yuanming
(Carmel, IN), Rieder; Brent J. (Greenfield, IN) |
Assignee: |
Dow AgroSciences, LLC.
(Indianapolis, IN)
|
Family
ID: |
41259492 |
Appl.
No.: |
12/550,952 |
Filed: |
August 31, 2009 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20100056374 A1 |
Mar 4, 2010 |
|
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
61092968 |
Aug 29, 2008 |
|
|
|
|
Current U.S.
Class: |
514/266.3;
514/266.4; 544/287; 544/293 |
Current CPC
Class: |
A61P
33/14 (20180101); A61P 33/00 (20180101); C07D
239/94 (20130101); A61P 33/02 (20180101); C07D
403/12 (20130101); A61P 33/10 (20180101); C07D
401/12 (20130101); A61P 5/00 (20180101); A61P
33/04 (20180101) |
Current International
Class: |
A61K
31/517 (20060101) |
Field of
Search: |
;544/287,293 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0326328 |
|
Aug 1989 |
|
EP |
|
2036025 |
|
Jun 1980 |
|
GB |
|
WO93/04583 |
|
Mar 1993 |
|
WO |
|
WO94/04526 |
|
Mar 1994 |
|
WO |
|
WO94/04527 |
|
Mar 1994 |
|
WO |
|
WO97/38979 |
|
Oct 1997 |
|
WO |
|
WO 97-38979 |
|
Oct 1997 |
|
WO |
|
Primary Examiner: Wilson; James O
Assistant Examiner: McDowell; Brian
Attorney, Agent or Firm: Arnett; Charles W. Faegre Baker
Daniels LLP
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent
Application Ser. No. 61/092,968 filed Aug. 29, 2008.
Claims
The invention claimed is:
1. A compound of formula (I) ##STR00201## wherein: R represents H,
CH.sub.3, or a heterocycle selected from the group consisting of
pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl wherein the
heterocycle may be optionally substituted with one or more groups
selected from halo, lower alkyl, lower alkenyl, lower alkynyl,
lower alkoxy, haloalkyl, haloalkoxy, NO.sub.2, CN, lower
alkoxycarbonyl, and lower alkyl-SO.sub.q, when q is an integer from
0 to 2; Z represents a C--C single bond, CH.sub.2, NH, O, S,
--CH.sub.2O--, or --OCH.sub.2--; m is 4; R.sup.1 are independently
H, halo, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower
alkoxy, haloalkyl, haloalkoxy, NO.sub.2, CN, lower alkoxycarbonyl,
mercapto, or lower alkylthio; Y is a C--C single bond,
C(R.sup.7.sub.n)O or C(R.sup.7.sub.n); n is 2; R.sup.2 are
independently H or lower alkyl; R.sup.7 are independently H or
lower alkyl; X is NR.sup.3 or O, where R.sup.3 is selected from H,
lower alkyl, lower alkyl-carbonyl, lower alkoxycarbonyl, hydroxy,
lower alkoxy, lower alkyl-SO.sub.q, phenyl-SO.sub.q or substituted
phenyl-SO.sub.q when q is an integer from 0 to 2; and R.sup.4 is H
or F; with the proviso that when Y is C(R.sup.7.sub.n),
R.sup.2.sub.n and one of R.sup.1 may be taken together to form a
compound of formula (II) ##STR00202##
2. A composition comprising a compound according to claim 1 in the
form of bait, concentrated emulsion, dust, emulsifiable
concentrate, fumigant, gel, granule, microencapsulation, seed
treatment, suspension concentrate, suspoemulsion, tablet, water
soluble liquid, water dispersible granule, wettable powder, or
ultra low volume solution.
Description
FIELD OF THE INVENTION
The present disclosure relates to
5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines
and their use as agrochemicals and animal health products.
BACKGROUND AND SUMMARY
The present disclosure provides novel organic compounds that may
demonstrate control of fungi, insects, mites, and animal parasites.
The disclosure also provides novel pesticide methods and
compositions utilizing the novel compounds.
More specifically, the invention provides new compounds of the
formula (I):
##STR00001## wherein:
R represents H, CH.sub.3, or a heterocycle selected from the group
consisting of pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl
wherein the heterocycle may be optionally substituted with one or
more groups selected from halo, lower alkyl, lower alkenyl, lower
alkynyl, lower alkoxy, haloalkyl, haloalkoxy, NO.sub.2, CN, lower
alkoxycarbonyl, and lower alkyl-SO.sub.q, when q is an integer from
0 to 2;
Z represents a C-C single bond, CH.sub.2, NH, O, S, --CH.sub.2O--,
or --OCH.sub.2--;
m is 4;
R.sup.1 are independently H, halo, lower alkyl, lower alkenyl,
lower alkynyl, hydroxy, lower alkoxy, haloalkyl, haloalkoxy,
NO.sub.2, CN, lower alkoxycarbonyl, mercapto, or lower
alkylthio;
Y is a C-C single bond, C(R.sup.7.sub.n)O or C(R.sup.7.sub.n);
n is 2;
R.sup.2 are independently H or lower alkyl
R.sup.7 are independently H or lower alkyl;
X is NR.sup.3 or O, where R.sup.3 is selected from H, lower alkyl,
lower alkyl-carbonyl, lower alkoxycarbonyl, hydroxy, lower alkoxy,
lower alkyl-SO.sub.q, phenyl-SO.sub.q or substituted
phenyl-SO.sub.q when q is an integer from 0 to 2; and
R.sup.4 is H or F;
with the proviso that when Y is C(R.sup.7.sub.n), R.sup.2.sub.n and
one of R.sup.1 may be taken together to form a compound of formula
(I-C)
##STR00002##
The invention also provides new pesticide methods and compositions
utilizing the compounds of formula (I).
The invention includes fungicidal, insecticidal, acaricidal, and
anti-parasitic compositions comprising an effective amount of a
compound of the present invention in a mixture with an
agriculturally acceptable or pharmaceutically acceptable adjuvant
or carrier. The invention also includes methods of controlling a
fungus, insect, mite, or parasite comprising applying an effective
amount of a compound of the present invention to the fungus, insect
or mite, soil, plant, root, foliage, seed, locus, or animal (for
which purpose they may be administered orally, parenterally,
percutaneously or topically) in which the infestation is to be
prevented or cured.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are directed to compounds of
formula (I)
##STR00003## wherein R may be an optionally substituted
six-membered heterocyclic system containing one or two nitrogen
atoms. More specifically, R may be selected from:
optionally substituted pyridinyl
##STR00004##
optionally substituted pyrazinyl
##STR00005##
optionally substituted pyrimidinyl
##STR00006##
optionally substituted pyridazinyl
##STR00007## where p is 4 in the case of pyridinyl and 3 in the
case of pyrazinyl, pyrimidinyl, and pyridazinyl, and R.sup.5 are
independently H, halo, lower alkyl, lower alkoxy, lower alkenyl,
lower alkynyl, haloalkyl, haloalkoxy, NO.sub.2, CN, lower
alkoxycarbonyl and lower alkyl-SO.sub.q and q is an integer from 0
to 2.
Throughout this document, all temperatures are given in degrees
Celsius, and all percentages are weight percentages unless
otherwise stated.
The terms "alkyl", "alkenyl" and "alkynyl", as well as derivative
terms such as "alkoxy" and "alkylthio", as used herein, include
within their scope straight chain, branched chain and cyclic
moieties. The terms "alkenyl" and "alkynyl" are intended to include
one or more unsaturated bonds.
The term "halo" refers to F, Cl, Br, and I atoms.
The term "lower alkyl" refers to C.sub.1 to C.sub.6 straight
hydrocarbon chains and C.sub.3 to C.sub.6 branched and cyclic
hydrocarbon groups.
The terms "lower alkenyl" and "lower alkynyl" refer to C.sub.2 to
C.sub.6 straight hydrocarbon chains and C.sub.3 (or C.sub.4 in the
case of lower alkynyl) to C.sub.6 branched hydrocarbon groups
containing at least one unsaturated bond.
The terms "lower alkoxy" and "lower alkylthio" refer to O-lower
alkyl and S-lower alkyl groups.
The term "haloalkyl" refers to lower alkyl groups substituted with
one or more halo atoms.
The term "haloalkoxy" refers to lower alkoxy groups substituted
with one or more halo atoms.
The term "substituted phenyl" refers to phenyl substituted with
lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower
alkylthio, halo, hydroxy, NO.sub.2, haloalkyl, haloalkoxy,
haloalkylthio, CN, phenyl, substituted phenyl, O-phenyl,
O-substituted phenyl, C.sub.1-C.sub.4 alkanoyloxy, C.sub.1-C.sub.4
alkoxycarbonyl, benzyloxy, or and lower alkyl-SO.sub.q and q is an
integer from 0 to 2.
In the present invention, whenever multiple substituents are
independently selected it is to be understood that they are
selected so as to be sterically compatible with each other. Steric
compatibility refers to the absence of steric hindrance as this
term is defined in The Condensed Chemical Dictionary, 7th edition,
Reinhold Publishing Co., N.Y. page 893 (1966), which definition is
as follows: steric hindrance. A characteristic of molecular
structure in which the molecules have a spatial arrangement of
their atoms such that a given reaction with another molecule is
prevented or retarded in rate. Steric compatibility is
characterized by substituents whose physical bulk does not require
confinement within volumes insufficient for the exercise of their
normal behavior as discussed in D. J. Cram and G. Hammond, Organic
Chemistry 2nd edition, McGraw-Hill Book Company, N.Y. page 215
(1964).
The compounds of this invention are made using well known chemical
procedures. The required starting materials are commercially
available or are readily synthesized using standard procedures.
Synthesis of Compounds (I) Wherein X is O
##STR00008##
The compounds of formula (I) wherein X is O (I-A) can be made by
condensing a compound of formula (II)
##STR00009## where R.sup.4 is as defined as for formula (I); and L
is a leaving group, such as F, Cl, Br, I, NO.sub.2,
1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, OSiMe.sub.3, arylthio,
alkylthio, alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl, or
arylsulfinyl; with a compound of the formula (III)
##STR00010## where R, Y, Z, R.sup.1, R.sup.2, m and n are as
defined for formula (I) and X is O. The reaction is preferably
carried out in the presence of a base in a non-reactive solvent,
such as dichloromethane, THF or DMF, at a temperature in the range
of 0.degree. to reflux temperature.
Synthesis of Compounds (I) Wherein X is NH or N-Lower Alkyl
##STR00011##
The compounds of formula (I) wherein X is NH or N-lower alkyl and Z
is oxygen (I-B), can be made by condensing a compound of formula
(II)
##STR00012## where R.sup.4 is as defined as for formula (I); and L
is a leaving group, such as F, Cl, Br, I, NO.sub.2,
1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, OSiMe.sub.3, arylthio,
alkylthio, alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl, or
arylsulfinyl; with a compound of the formula (III)
##STR00013## where R, Y, Z, R.sup.1, R.sup.2, m and n are as
defined for formula (I) and X is NH or N-lower alkyl optionally as
a salt (e.g., HCl). The reaction is preferably carried out in the
presence of base, such as triethylamine, in a non-reactive solvent,
such as dichloromethane, THF or DMF.
##STR00014##
The compounds of formula (I) wherein X is NH or N-lower alkyl and Z
is oxygen (I-B) where R is a heterocycle selected from the group
consisting of pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl
wherein the heterocycle may be optionally substituted with one or
more groups selected from halo, lower alkyl, lower alkenyl, lower
alkynyl, lower alkoxy, haloalkyl, haloalkoxy, NO.sub.2, CN, lower
alkoxycarbonyl, and lower alkyl-SO.sub.q, when q is an integer from
0 to 2;
alternatively are prepared by treatment of a compound of formula
(IV)
##STR00015## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y, m and n
are as defined for formula (I); with a heterocycle of formula
L-Het
where L is as defined for formula (II) and Het is a heterocycle
selected from the group consisting of pyridinyl, pyrazinyl,
pyrimidinyl, or pyridazinyl wherein the heterocycle may be
optionally substituted with one or more groups selected from halo,
lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, haloalkyl,
haloalkoxy, NO.sub.2, CN, lower alkoxycarbonyl, and lower
alkyl-SO.sub.q, when q is an integer from 0 to 2.
The reaction is preferably carried out in the presence of a base,
such as sodium hydride, in a nonreactive solvent, such as DMF.
Certain compounds (I) are prepared by modifications of other
compounds (I), as described in the Examples shown in the following
section.
The compounds of formula (IV) may be prepared by treatment of
compounds of formula (V)
##STR00016## where R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y, m and n
are as defined for formula (I), and R.sup.6 is lower alkyl; with a
reagent such as BBr.sub.3 in a nonreactive organic solvent, such as
dichloromethane.
The compounds of formula (IV) alternatively may be prepared by
treatment of compounds of formula (VI) wherein R.sup.4 is as
described for compound (I),
##STR00017## with a compound of formula (VII), optionally as a salt
(e.g., HCl),
##STR00018## where R.sup.1, R.sup.2, Y, m and n are as defined for
formula (I), and R.sup.3 is H; in the presence of acetic acid,
optionally as a solution in an appropriate solvent such as ethanol;
with heating at temperatures from 25.degree. to reflux.
The compounds of formula (IV) alternatively may be prepared by
treatment of compounds of formula (II)
##STR00019## where R.sup.4 is as defined as for formula (I); and L
is a leaving group, such as F, Cl, Br, I, NO.sub.2,
1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, OSiMe.sub.3, arylthio,
alkylthio, alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl or
arylsulfinyl; with a compound of formula (VII), optionally as a
salt (e.g., HCl),
##STR00020## where R.sup.1, R.sup.2, R.sup.3, Y, m and n are as
defined for formula (I); optionally in the presence of a base, in a
solvent such as acetonitrile, THF or DMF.
Compounds of formula (V) are prepared by the treatment of compounds
of formula (VI) wherein R.sup.4 is as described for compound (I);
with a compound of formula (VIII), optionally as a salt (e.g.,
HCl),
##STR00021## where R.sup.1, R.sup.2, Y, m and n are as defined for
formula (I), R.sup.3 is H, and R.sup.6 is lower alkyl as defined
for formula (I); in the presence of acetic acid, optionally as a
solution in an appropriate solvent such as ethanol; with heating at
temperatures from 25.degree. to reflux.
Amines of formula (VIII) where R.sup.1, R.sup.2, R.sup.3, Y, m and
n are as defined for formula (I) and R.sup.6 is lower alkyl as
defined for formula (I); are commercially available or may be
prepared by well-known methods. For example, compounds of formula
(VIII), where R.sup.1, R.sup.2, m and n are as defined for formula
(I), R.sup.6 is lower alkyl, R.sup.3 is H, and Y is R.sup.7.sub.n
are prepared as their hydrochloride salts by treatment of
appropriately substituted (4-alkoxyphenyl)-acetonitriles with
hydrogen in the presence of hydrochloric acid, a catalyst such as
palladium on carbon, and an appropriate solvent such as
ethanol.
Alternatively, compounds of formula (VIII), where R.sup.1, R.sup.2,
m and n are as defined for formula (I), R.sup.6 is lower alkyl,
R.sup.3 is H, Y is R.sup.7.sub.n are prepared by treatment of
appropriately substituted (4-alkoxyphenyl)-acetonitriles with
borane-dimethyl sulfide complex in an appropriate solvent such as
tetrahydrofuran at temperatures from 20.degree. C. to reflux.
Alternatively, compounds of formula (VIII), where R.sup.1, R.sup.2,
m and n are as defined for formula (I), R.sup.6 is lower alkyl,
R.sup.3 is H, and Y is R.sup.7.sub.n are prepared as their
hydrochloride salts by treatment of appropriately substituted
1-alkoxy-4-((E)-2-nitrovinyl)-benzenes with hydrogen in the
presence of hydrochloric acid, a catalyst such as palladium on
carbon, and an appropriate solvent such as ethanol.
Alternatively, compounds of formula (VIII), where R.sup.1, R.sup.2,
m and n are as defined for formula (I), R.sup.6 is alkyl or benzyl,
R.sup.3 is H, and Y is R.sup.7.sub.n are prepared by treatment of
the appropriately substituted
1-alkoxy-4-((E)-2-nitrovinyl)-benzenes with lithium aluminum
hydride in an appropriate solvent such as tetrahydrofuran.
The 1-alkoxy-4-((E)-2-nitrovinyl)-benzenes are prepared by
treatment of the appropriately substituted benzaldehyde with
nitromethane in the presence of ammonium acetate.
The compounds of formula (I) wherein X is NH (namely, formula I-B
where R.sup.3 is H) alternatively are prepared by treatment of a
compound of formula (VI), as defined above, with a compound of
formula (III), optionally as a salt (e.g., HCl), where R, Z,
R.sup.1, R.sup.2, m and n are as defined for formula (I) and X is
NH; in the presence of acetic acid, optionally as a solution in an
appropriate solvent such as ethanol; with heating at temperatures
from 25.degree. to reflux.
Compounds of formula (VI)
##STR00022## where R.sup.4 is as described for compound (I) were
prepared by treatment of a compound of formula (IX)
##STR00023## where R.sup.4 is as defined for (I), with
N,N-dimethylformamide dimethyl acetal in an appropriate solvent
such as toluene, with heating at temperature from 25.degree. C. up
to the reflux temperature.
Compounds of formula (IX)
##STR00024## where R.sup.4 is as defined for (I) were prepared by
treatment of compounds of formula (X)
##STR00025## where R.sup.4 is as defined for (I), with ammonium
hydroxide solution at a temperature of 25 to 100.degree..
The compounds of the present invention may have fungitoxic activity
against harmful fungi including, but not limited to, fungi that are
pathogens of plants, animals, and humans. They are active against
fungi of a number of classes including Oomycetes, Deuteromycetes
(Fungi Imperfecti), Basidiomycetes, and Ascomycetes. More
particularly, one embodiment of a method of the present invention
provides for activity against phytopathogenic organisms including,
but not limited to, Pyricularia oryzae, Colletotrichum species,
Eysiphe species, Puccinia species, Helminthosporium species,
Alternaria species, Septoria species, Rhynchosporium secalis,
Cercospora and Cercosporella species, and Pyrenophora species.
Additional diseases controlled include powdery mildews incited by
Sphaerotheca fulignea (cucurbit powdery mildew) and Uncinula
necator (grape powdery mildew), soybean rust incited by Phakopsora
pachyrhizi, downy mildews such as cucumber downy mildew
(Pseudoperonospora cubensis), grape downy mildew (Plasmopara
viticola), apple scab incited by Venturia inaequalis, and late
blight incited by Phytophthora infestans.
The compounds of the present invention may have insecticidal
activity against harmful insects and mites including, but not
limited to, insects that are pests or parasites of plants, animals,
and humans.
In other embodiments, the invention disclosed in this document may
be used to control pests of Phylum Nematoda, the Phylum Arthropoda,
the Subphylum Chelicerata, the Class Arachnida, the Subphylum
Myriapoda, the Class Symphyla, the Subphylum Hexapoda, the Class
Insecta, and Coleoptera (beetles). A non-exhaustive list of these
such pests includes, but is not limited to, Acanthoscelides spp.
(weevils), Acanthoscelides obtectus (common bean weevil), Agrilus
planipennis (emerald ash borer), Agriotes spp. (wireworms),
Anoplophora glabripennis (Asian longhorned beetle), Anthonomus spp.
(weevils), Anthonomus grandis (boll weevil), Aphidius spp., Apion
spp. (weevils), Apogonia spp. (grubs), Ataenius spretulus (Black
Turgrass Ataenius), Atomaria linearis (pygmy mangold beetle),
Aulacophore spp., Bothynoderes punctiventris (beet root weevil),
Bruchus spp. (weevils), Bruchus pisorum (pea weevil), Cacoesia
spp., Callosobruchus maculatus (southern cow pea weevil),
Carpophilus hemipteras (dried fruit beetle), Cassida vittata,
Cerosterna spp, Cerotoma spp. (chrysomeids), Cerotoma trifurcata
(bean leaf beetle), Ceutorhynchus spp. (weevils), Ceutorhynchus
assimilis (cabbage seedpod weevil), Ceutorhynchus napi (cabbage
curculio), Chaetocnema spp. (chrysomelids), Colaspis spp. (soil
beetles), Conoderus scalaris, Conoderus stigmosus, Conotrachelus
nenuphar (plum curculio), Cotinus nitidis (Green June beetle),
Crioceris asparagi (asparagus beetle), Cryptolestes ferrugineus
(rusty grain beetle), Cryptolestes pusillus (flat grain beetle),
Cryptolestes turcicus (Turkish grain beetle), Ctenicera spp.
(wireworms), Curculio spp. (weevils), Cyclocephala spp. (grubs),
Cylindrocpturus adspersus (sunflower stem weevil), Deporaus
marginatus (mango leaf-cutting weevil), Dermestes lardarius (larder
beetle), Dermestes maculates (hide beetle), Diabrotica spp.
(chrysolemids), Epilachna varivestis (Mexican bean beetle),
Faustinus cubae, Hylobius pales (pales weevil), Hypera spp.
(weevils), Hypera postica (alfalfa weevil), Hyperodes spp.
(Hyperodes weevil), Hypothenemus hampei (coffee berry beetle), Ips
spp. (engravers), Lasioderma serricorne (cigarette beetle),
Leptinotarsa decemlineata (Colorado potato beetle), Liogenys
fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus (rice water
weevil), Lyctus spp. (wood beetles/powder post beetles),
Maecolaspis joliveti, Megascelis spp., Melanotus communis,
Meligethes spp., Meligethes aeneus (blossom beetle), Melolontha
melolontha (common European cockchafer), Oberea brevis, Oberea
linearis, Oryctes rhinoceros (date palm beetle), Oryzaephilus
mercator (merchant grain beetle), Oryzaephilus surinamensis
(sawtoothed grain beetle), Otiorhynchus spp. (weevils), Oulema
melanopus (cereal leaf beetle), Oulema oryzae, Pantomorus spp.
(weevils), Phyllophaga spp. (May/June beetle), Phyllophaga
cuyabana, Phyllotreta spp. (chrysomelids), Phynchites spp.,
Popillia japonica (Japanese beetle), Prostephanus truncates (larger
grain borer), Rhizopertha dominica (lesser grain borer),
Rhizotrogus spp. (European chafer), Rhynchophorus spp. (weevils),
Scolytus spp. (wood beetles), Shenophorus spp. (Billbug), Sitona
lineatus (pea leaf weevil), Sitophilus spp. (grain weevils),
Sitophilus granaries (granary weevil), Sitophilus oryzae (rice
weevil), Stegobium paniceum (drugstore beetle), Tribolium spp.
(flour beetles), Tribolium castaneum (red flour beetle), Tribolium
confusum (confused flour beetle), Trogoderma variabile (warehouse
beetle), and Zabrus tenebioides.
In another embodiment, the invention disclosed in this document may
be used to control Dermaptera (earwigs).
In another embodiment, the invention disclosed in this document may
be used to control Dictyoptera (cockroaches). A non-exhaustive list
of such pests includes, but is not limited to, Blattella germanica
(German cockroach), Blatta orientalis (oriental cockroach),
Parcoblatta pennylvanica, Periplaneta americana (American
cockroach), Periplaneta australoasiae (Australian cockroach),
Periplaneta brunnea (brown cockroach), Periplaneta fuliginosa
(smokybrown cockroach), Pyncoselus suninamensis (Surinam
cockroach), and Supella longipalpa (brownbanded cockroach).
In another embodiment, the invention disclosed in this document may
be used to control Diptera (true flies). A non-exhaustive list of
such pests includes, but is not limited to, Aedes spp.
(mosquitoes), Agromyza frontella (alfalfa blotch leafminer),
Agromyza spp. (leaf miner flies), Anastrepha spp. (fruit flies),
Anastrepha suspensa (Caribbean fruit fly), Anopheles spp.
(mosquitoes), Batrocera spp. (fruit flies), Bactrocera cucurbitae
(melon fly), Bactrocera dorsalis (oriental fruit fly), Ceratitis
spp. (fruit flies), Ceratitis capitata (Mediterranea fruit fly),
Chrysops spp. (deer flies), Cochliomyia spp. (screwworms),
Contarinia spp. (Gall midges), Culex spp. (mosquitoes), Dasineura
spp. (gall midges), Dasineura brassicae (cabbage gall midge), Delia
spp., Delia platura (seedcorn maggot), Drosophila spp. (vinegar
flies), Fannia spp. (filth flies), Fannia canicularis (little house
fly), Fannia scalaris (latrine fly), Gasterophilus intestinalis
(horse bot fly), Gracillia perseae, Haematobia irritans (horn fly),
Hylemyia spp. (root maggots), Hypoderma lineatum (common cattle
grub), Liriomyza spp. (leafminer flies), Liriomyza brassica
(serpentine leafminer), Melophagus ovinus (sheep ked), Musca spp.
(muscid flies), Musca autumnalis (face fly), Musca domestica (house
fly), Oestrus ovis (sheep bot fly), Oscinella frit (frit fly),
Pegomyia betae (beet leafminer), Phorbia spp., Psila rosae (carrot
rust fly), Rhagoletis cerasi (cherry fruit fly), Rhagoletis
pomonella (apple maggot), Sitodiplosis mosellana (orange wheat
blossom midge), Stomoxys calcitrans (stable fly), Tabanus spp.
(horse flies), and Tipula spp. (crane flies).
In another embodiment, the invention disclosed in this document may
be used to control Hemiptera (true bugs). A non-exhaustive list of
such pests includes, but is not limited to, Acrosternum hilare
(green stink bug), Blissus leucopterus (chinch bug), Calocoris
norvegicus (potato mirid), Cimex hemipterus (tropical bed bug),
Cimex lectularius (bed bug), Dagbertus fasciatus, Dichelops
furcatus, Dysdercus suturellus (cotton stainer), Edessa
meditabunda, Eurygaster maura (cereal bug), Euschistus heros,
Euschistus servus (brown stink bug), Helopeltis antonii, Helopeltis
theivora (tea blight plantbug), Lagynotomus spp. (stink bugs),
Leptocorisa oratorius, Leptocorisa varicornis, Lygus spp. (plant
bugs), Lygus hesperus (western tarnished plant bug),
Maconellicoccus hirsutus, Neurocolpus longirostris, Nezara viridula
(southern green stink bug), Phytocoris spp. (plant bugs),
Phytocoris californicus, Phytocoris relativus, Piezodorus
guildingi, Poecilocapsus lineatus (fourlined plant bug), Psallus
vaccinicola, Pseudacysta perseae, Scaptocoris castanea, and
Triatoma spp. (bloodsucking conenose bugs/kissing bugs).
In another embodiment, the invention disclosed in this document may
be used to control Homoptera (aphids, scales, whiteflies,
leafhoppers). A non-exhaustive list of such pests includes, but is
not limited to, Acrythosiphon pisum (pea aphid), Adelges spp.
(adelgids), Aleurodes proletella (cabbage whitefly), Aleurodicus
disperses, Aleurothrixus floccosus (woolly whitefly), Aluacaspis
spp., Amrasca bigutella bigutella, Aphrophora spp. (leafhoppers),
Aonidiella aurantii (California red scale), Aphis spp. (aphids),
Aphis gossypii (cotton aphid), Aphis pomi (apple aphid),
Aulacorthum solani (foxglove aphid), Bemisia spp. (whiteflies),
Bemisia argentifolii, Bemisia tabaci (sweetpotato whitefly),
Brachycolus noxius (Russian aphid), Brachycorynella asparagi
(asparagus aphid), Brevennia rehi, Brevicoryne brassicae (cabbage
aphid), Ceroplastes spp. (scales), Ceroplastes rubens (red wax
scale), Chionaspis spp. (scales), Chrysomphalus spp. (scales),
Coccus spp. (scales), Dysaphis plantaginea (rosy apple aphid),
Empoasca spp. (leafhoppers), Eriosoma lanigerum (woolly apple
aphid), Icerya purchasi (cottony cushion scale), Idioscopus
nitidulus (mango leafhopper), Laodelphax striatellus (smaller brown
planthopper), Lepidosaphes spp., Macrosiphum spp., Macrosiphum
euphorbiae (potato aphid), Macrosiphum granarium (English grain
aphid), Macrosiphum rosae (rose aphid), Macrosteles quadrilineatus
(aster leafhopper), Mahanarva frimbiolata, Metopolophium dirhodum
(rose grain aphid), Mictis longicoruis, Myzus persicae (green peach
aphid), Nephotettix spp. (leafhoppers), Nephotettix cinctipes
(green leafhopper), Nilaparvata lugens (brown planthopper),
Parlatoria pergandii (chaff scale), Parlatoria ziziphi (ebony
scale), Peregrinus maidis (corn delphacid), Philaenus spp.
(spittlebugs), Phylloxera vitifoliae (grape phylloxera),
Physokermes piceae (spruce bud scale), Planococcus spp.
(mealybugs), Pseudococcus spp. (mealybugs), Pseudococcus brevipes
(pine apple mealybug), Quadraspidiotus perniciosus (San Jose
scale), Rhapalosiphum spp. (aphids), Rhapalosiphum maida (corn leaf
aphid), Rhapalosiphum padi (oat bird-cherry aphid), Saissetia spp.
(scales), Saissetia oleae (black scale), Schizaphis graminum
(greenbug), Sitobion avenae (English grain aphid), Sogatella
furcifera (white-backed planthopper), Therioaphis spp. (aphids),
Toumeyella spp. (scales), Toxoptera spp. (aphids), Trialeurodes
spp. (whiteflies), Trialeurodes vaporariorum (greenhouse whitefly),
Trialeurodes abutiloneus (bandedwing whitefly), Unaspis spp.
(scales), Unaspis yanonensis (arrowhead scale), and Zulia
entreriana.
In another embodiment, the invention disclosed in this document may
be used to control Hymenoptera (ants, wasps, and bees). A
non-exhaustive list of such pests includes, but is not limited to,
Acromyrrmex spp., Athalia rosae, Atta spp. (leafcutting ants),
Camponotus spp. (carpenter ants), Diprion spp. (sawflies), Formica
spp. (ants), Iridomyrmex humilis (Argentine ant), Monomorium ssp.,
Monomorium minumum (little black ant), Monomorium pharaonis
(Pharaoh ant), Neodiprion spp. (sawflies), Pogonomyrmex spp.
(harvester ants), Polistes spp. (paper wasps), Solenopsis spp.
(fire ants), Tapoinoma sessile (odorous house ant), Tetranomorium
spp. (pavement ants), Vespula spp. (yellow jackets), and Xylocopa
spp. (carpenter bees).
In another embodiment, the invention disclosed in this document may
be used to control Isoptera (termites). A non-exhaustive list of
such pests includes, but is not limited to, Coptotermes spp.,
Coptotermes curvignathus, Coptotermes frenchii, Coptotermes
formosanus (Formosan subterranean termite), Cornitermes spp.
(nasute termites), Cryptotermes spp. (drywood termites),
Heterotermes spp. (desert subterranean termites), Heterotermes
aureus, Kalotermes spp. (drywood termites), Incistitermes spp.
(drywood termites), Macrotermes spp. (fungus growing termites),
Marginitermes spp. (drywood termites), Microcerotermes spp.
(harvester termites), Microtermes obesi, Procornitermes spp.,
Reticulitermes spp. (subterranean termites), Reticulitermes
banyulensis, Reticulitermes grassei, Reticulitermes flavipes
(eastern subterranean termite), Reticulitermes hageni,
Reticulitermes hesperus (western subterranean termite),
Reticulitermes santonensis, Reticulitermes speratus, Reticulitermes
tibialis, Reticulitermes virginicus, Schedorhinotermes spp., and
Zootermopsis spp. (rotten-wood termites).
In another embodiment, the invention disclosed in this document may
be used to control Lepidoptera (moths and butterflies). A
non-exhaustive list of such pests includes, but is not limited to,
Achoea janata, Adoxophyes spp., Adoxophyes orana, Agrotis spp.
(cutworms), Agrotis ipsilon (black cutworm), Alabama argillacea
(cotton leafworm), Amorbia cuneana, Amyelosis transitella (navel
orangeworm), Anacamptodes defectaria, Anarsia lineatella (peach
twig borer), Anomis sabulifera (jute looper), Anticarsia gemmatalis
(velvetbean caterpillar), Archips argyrospila (fruittree
leafroller), Archips rosana (rose leaf roller), Argyrotaenia spp.
(tortricid moths), Argyrotaenia citrana (orange tortrix),
Autographa gamma, Bonagota cranaodes, Borbo cinnara (rice leaf
folder), Bucculatrix thurberiella (cotton leafperforator),
Caloptilia spp. (leaf miners), Capua reticulana, Carposina
niponensis (peach fruit moth), Chilo spp., Chlumetia transversa
(mango shoot borer), Choristoneura rosaceana (obliquebanded
leafroller), Chrysodeixis spp., Cnaphalocerus medinalis (grass
leafroller), Colias spp., Conpomorpha cramerella, Cossus cossus
(carpenter moth), Crambus spp. (Sod webworms), Cydia funebrana
(plum fruit moth), Cydia molesta (oriental fruit moth), Cydia
nignicana (pea moth), Cydia pomonella (codling moth), Darna
diducta, Diaphania spp. (stem borers), Diatraea spp. (stalk
borers), Diatraea saccharalis (sugarcane borer), Diatraea
graniosella (southwester corn borer), Earias spp. (bollworms),
Earias insulata (Egyptian bollworm), Earias vitella (rough northern
bollworm), Ecdytopopha aurantianum, Elasmopalpus lignosellus
(lesser cornstalk borer), Epiphysias postruttana (light brown apple
moth), Ephestia spp. (flour moths), Ephestia cautella (almond
moth), Ephestia elutella (tobacco moth), Ephestia kuehniella
(Mediterranean flour moth), Epimeces spp., Epinotia aporema,
Erionota thrax (banana skipper), Eupoecilia ambiguella (grape berry
moth), Euxoa auxiliaris (army cutworm), Feltia spp. (cutworms),
Gortyna spp. (stemborers), Grapholita molesta (oriental fruit
moth), Hedylepta indicata (bean leaf webber), Helicoverpa spp.
(noctuid moths), Helicoverpa armigera (cotton bollworm),
Helicoverpa zea (bollworm/corn earworm), Heliothis spp. (noctuid
moths), Heliothis virescens (tobacco budworm), Hellula undalis
(cabbage webworm), Indarbela spp. (root borers), Keiferia
lycopersicella (tomato pinworm), Leucinodes orbonalis (eggplant
fruit borer), Leucoptera malifoliella, Lithocollectis spp., Lobesia
botrana (grape fruit moth), Loxagrotis spp. (noctuid moths),
Loxagrotis albicosta (western bean cutworm), Lymantria dispar
(gypsy moth), Lyonetia clerkella (apple leaf miner), Mahasena
corbetti (oil palm bagworm), Malacosoma spp. (tent caterpillars),
Mamestra brassicae (cabbage armyworm), Maruca testulalis (bean pod
borer), Metisa plana (bagworm), Mythimna unipuncta (true armyworm),
Neoleucinodes elegantalis (small tomato borer), Nymphula
depunctalis (rice caseworm), Operophthera brumata (winter moth),
Ostrinia nubilalis (European corn borer), Oxydia vesulia, Pandemis
cerasana (common currant tortrix), Pandemis heparana (brown apple
tortrix), Papilio demodocus, Pectinophora gossypiella (pink
bollworm), Peridroma spp. (cutworms), Peridroma saucia (variegated
cutworm), Perileucoptera coffeella (white coffee leafminer),
Phthorimaea operculella (potato tuber moth), Phyllocnisitis
citrella, Phyllonorycter spp. (leafminers), Pieris rapae (imported
cabbageworm), Plathypena scabra, Plodia interpunctella (Indian meal
moth), Plutella xylostella (diamondback moth), Polychrosis viteana
(grape berry moth), Prays endocarpa, Prays oleae (olive moth),
Pseudaletia spp. (noctuid moths), Pseudaletia unipunctata
(armyworm), Pseudoplusia includens (soybean looper), Rachiplusia
nu, Scirpophaga incertulas, Sesamia spp. (stemborers), Sesamia
inferens (pink rice stem borer), Sesamia nonagrioides, Setora
nitens, Sitotroga cerealella (Angoumois grain moth), Sparganothis
pilleriana, Spodoptera spp. (armyworms), Spodoptera exigua (beet
armyworm), Spodoptera fugiperda (fall armyworm), Spodoptera
oridania (southern armyworm), Synanthedon spp. (root borers),
Thecla basilides, Thermisia gemmatalis, Tineola bisselliella
(webbing clothes moth), Trichoplusia ni (cabbage looper), Tuta
absoluta, Yponomeuta spp., Zeuzera coffeae (red branch borer), and
Zeuzera pyrina (leopard moth).
In another embodiment, the invention disclosed in this document may
be used to control Mallophaga (chewing lice). A non-exhaustive list
of such pests includes, but is not limited to, Bovicola ovis (sheep
biting louse), Menacanthus stramineus (chicken body louse), and
Menopon gallinea (common hen house).
In another embodiment, the invention disclosed in this document may
be used to control Orthoptera (grasshoppers, locusts, and
crickets). A non-exhaustive list of such pests includes, but is not
limited to, Anabrus simplex (Mormon cricket), Gryllotalpidae (mole
crickets), Locusta migratoria, Melanoplus spp. (grasshoppers),
Microcentrum retinerve (angularwinged katydid), Pterophylla spp.
(kaydids), chistocerca gregaria, Scudderia furcata (forktailed bush
katydid), and Valanga nigricorni.
In another embodiment, the invention disclosed in this document may
be used to control Phthiraptera (sucking lice). A non-exhaustive
list of such pests includes, but is not limited to, Haematopinus
spp. (cattle and hog lice), Linognathus ovillus (sheep louse),
Pediculus humanus capitis (human body louse), Pediculus humanus
humanus (human body lice), and Phtirus pubis (crab louse),
In another embodiment, the invention disclosed in this document may
be used to control Siphonaptera (fleas). A non-exhaustive list of
such pests includes, but is not limited to, Ctenocephalides canis
(dog flea), Ctenocephalides felis (cat flea), and Pulex irritans
(human flea).
In another embodiment, the invention disclosed in this document may
be used to control Thysanoptera (thrips). A non-exhaustive list of
such pests includes, but is not limited to, Frankliniella fusca
(tobacco thrips), Frankliniella occidentalis (western flower
thrips), Frankliniella shultzei Frankliniella williamsi (corn
thrips), Heliothrips haemorrhaidalis (greenhouse thrips),
Riphiphorothrips cruentatus, Scirtothrips spp., Scirtothrips citri
(citrus thrips), Scirtothrips dorsalis (yellow tea thrips),
Taeniothrips rhopalantennalis, and Thrips spp.
In another embodiment, the invention disclosed in this document may
be used to control Thysanura (bristletails). A non-exhaustive list
of such pests includes, but is not limited to, Lepisma spp.
(silverfish) and Thermobia spp. (firebrats).
In another embodiment, the invention disclosed in this document may
be used to control Acarina (mites and ticks). A non-exhaustive list
of such pests includes, but is not limited to, Acarapsis woodi
(tracheal mite of honeybees), Acarus spp. (food mites), Acarus siro
(grain mite), Aceria mangiferae (mango bud mite), Aculops spp.,
Aculops lycopersici (tomato russet mite), Aculops pelekasi, Aculus
pelekassi, Aculus schlechtendali (apple rust mite), Amblyomma
americanum (lone star tick), Boophilus spp. (ticks), Brevipalpus
obovatus (privet mite), Brevipalpus phoenicis (red and black flat
mite), Demodex spp. (mange mites), Dermacentor spp. (hard ticks),
Dermacentor variabilis (american dog tick), Dermatophagoides
pteronyssinus (house dust mite), Eotetranycus spp., Eotetranychus
carpini (yellow spider mite), Epitimerus spp., Eriophyes spp.,
Ixodes spp. (ticks), Metatetranycus spp., Notoedres cati,
Oligonychus spp., Oligonychus coffee, Oligonychus ilicus (southern
red mite), Panonychus spp., Panonychus citri (citrus red mite),
Panonychus ulmi (European red mite), Phyllocoptruta oleivora
(citrus rust mite), Polyphagotarsonemun latus (broad mite),
Rhipicephalus sanguineus (brown dog tick), Rhizoglyphus spp. (bulb
mites), Sarcoptes scabiei (itch mite), Tegolophus perseaflorae,
Tetranychus spp., Tetranychus urticae (twospotted spider mite), and
Varroa destructor (honey bee mite).
In another embodiment, the invention disclosed in this document may
be used to control Nematoda (nematodes). A non-exhaustive list of
such pests includes, but is not limited to, Aphelenchoides spp.
(bud and leaf & pine wood nematodes), Belonolaimus spp. (sting
nematodes), Criconemella spp. (ring nematodes), Dirofilaria immitis
(dog heartwom), Ditylenchus spp. (stem and bulb nematodes),
Heterodera spp. (cyst nematodes), Heterodera zeae (corn cyst
nematode), Hirschmanniella spp. (root nematodes), Hoplolaimus spp.
(lance nematodes), Meloidogyne spp. (root knot nematodes),
Meloidogyne incognita (root knot nematode), Onchocerca volvulus
(hook-tail worm), Pratylenchus spp. (lesion nematodes), Radopholus
spp. (burrowing nematodes), and Rotylenchus reniformis
(kidney-shaped nematode).
In another embodiment, the invention disclosed in this document may
be used to control Symphyla (symphylans). A non-exhaustive list of
such pests includes, but is not limited to, Scutigerella
immaculata.
In another embodiment, the invention disclosed in this document may
be used to control animal and human parasites. A non-exhaustive
list of such pests includes, but is not limited to, arthropods such
as mites (e.g., mesostigmatids, itch, mange, scabies, chiggers),
ticks (e.g., soft-bodied and hard-bodied), lice (e.g., sucking,
biting), fleas (e.g., dog flea, cat flea, oriental rat flea, human
flea), true bugs (e.g., bed bugs, Triatomid bugs), bloodsucking
adult flies (e.g., horn fly, horse fly, stable fly, black fly, deer
fly, louse fly, tsetse fly, mosquitoes), and parasitic fly maggots
(e.g, bot fly, blow fly, screwworn, cattle grub, fleeceworm);
helminths such as nematodes (e.g., threadworm, lungworm, hookworm,
whipworm, nodular worm, stomach worm, round worm, pinworm,
heartworm), cestodes (e.g., tapeworms) and trematodes (e.g., liver
fluke, blood fluke); protozoa such as coccidia, trypanosomes,
trichomonads, amoebas and plasmodia; acanthocephalans such as
thorny-headed worms (e.g., lingulatulida); and pentastomids such as
tongueworms.
Detailed information regarding pests may be found in the "Handbook
of Pest Control--The Behavior, Life History, and Control of
Household Pests" by Arnold Mallis, 9.sup.th Edition, copyright 2004
by GIE Media Inc, which is expressly incorporated by reference
herein.
The present invention contemplates all vehicles by which the
composition of the present invention can be formulated for delivery
and use as a pesticide composition, including solutions,
suspensions, emulsions, wettable powders and water dispersible
granules, emulsifiable concentrates, granules, dusts, baits, and
the like. Compositions suitable for administration to vertebrates
or man include preparations suitable for oral, parenteral,
percutaneous, e.g. pour-on, or topical administration.
Compositions for oral administration comprise one or more of the
compounds of general formula I in association with pharmaceutically
acceptable carriers or coatings and include, for example, tablets,
pills, capsules, pastes, gels, drenches, medicated feeds, medicated
drinking water, medicated dietary supplements, slow-release boluses
or other slow-release devices intended to be retained within the
gastro-intestinal tract. Any of these may incorporate active
ingredient contained within microcapsules or coated with
acid-labile or alkali-labile or other pharmaceutically acceptable
enteric coatings. Feed premixes and concentrates containing
compounds of the present invention for use in preparation of
medicated diets, drinking water or other materials for consumption
by animals may also be used.
Compositions for parenteral administration include solutions,
emulsions or suspensions in any suitable pharmaceutically
acceptable vehicle and solid or semisolid subcutaneous implants or
pellets designed to release active ingredient over a protracted
period and may be prepared and made sterile in any appropriate
manner known to the art.
Compositions for percutaneous and topical administration include
sprays, dusts, baths, dips, showers, jets, greases, shampoos,
creams, wax-smears, or pour-on preparations and devices (e.g. ear
tags) attached externally to animals in such a way as to provide
local or systemic arthropod control
Typically, formulations for application to plants or soil are
applied following dilution of the concentrated formulation with
water as aqueous solutions, suspensions or emulsions, or
combinations thereof. Such solutions, suspensions or emulsions are
produced from water-soluble, water-suspended or water-suspendable,
water-emulsified or water-emulsifiable formulations or combinations
thereof which are solids, including and usually known as wettable
powders or water dispersible granules; or liquids including and
usually known as emulsifiable concentrates, aqueous suspensions or
suspension concentrates, and aqueous emulsions or emulsions in
water, or mixtures thereof such as suspension-emulsions. As will be
readily appreciated, any material to which this composition can be
added may be used, provided they yield the desired utility without
significant interference with the desired activity of the
pesticidally active ingredients as pesticidal agents and improved
residual lifetime or decreased effective concentration is
achieved.
Wettable powders, which may be compacted to form water dispersible
granules, comprise an intimate mixture of one or more of the
pesticidally active ingredients, an inert carrier and surfactants.
The concentration of the pesticidally active ingredient in the
wettable powder is usually from about 10 percent to about 90
percent by weight based on the total weight of the wettable powder,
more preferably about 25 weight percent to about 75 weight percent.
In the preparation of wettable powder formulations, the
pesticidally active ingredients can be compounded with any finely
divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's
earth, bentonite, attapulgite, starch, casein, gluten,
montmorillonite clays, diatomaceous earths, purified silicates or
the like. In such operations, the finely divided carrier and
surfactants are typically blended with the compound(s) and
milled.
Emulsifiable concentrates of the pesticidally active ingredient
comprise a convenient concentration, such as from about 10 weight
percent to about 50 weight percent of the pesticidally active
ingredient, in a suitable liquid, based on the total weight of the
concentrate. The pesticidally active ingredients are dissolved in
an inert carrier, which is either a water miscible solvent or a
mixture of water-immiscible organic solvents, and emulsifiers. The
concentrates may be diluted with water and oil to form spray
mixtures in the form of oil-in-water emulsions. Useful organic
solvents include aromatics, especially the high-boiling
naphthalenic and olefinic portions of petroleum such as heavy
aromatic naphtha. Other organic solvents may also be used, such as,
for example, terpenic solvents, including rosin derivatives,
aliphatic ketones, such as cyclohexanone, and complex alcohols,
such as 2-ethoxyethanol.
Emulsifiers which can be advantageously employed herein can be
readily determined by those skilled in the art and include various
nonionic, anionic, cationic and amphoteric emulsifiers, or a blend
of two or more emulsifiers. Examples of nonionic emulsifiers useful
in preparing the emulsifiable concentrates include the polyalkylene
glycol ethers and condensation products of alkyl and aryl phenols,
aliphatic alcohols, aliphatic amines or fatty acids with ethylene
oxide, propylene oxides such as the ethoxylated alkyl phenols and
carboxylic esters esterified with the polyol or polyoxyalkylene.
Cationic emulsifiers include quaternary ammonium compounds and
fatty amine salts. Anionic emulsifiers include the oil-soluble
salts (e.g., calcium) of alkylaryl sulfonic acids, oil-soluble
salts of sulfated polyglycol ethers and appropriate salts of
phosphated polyglycol ether.
Representative organic liquids which can be employed in preparing
emulsifiable concentrates are the aromatic liquids such as xylene,
propyl benzene fractions; or mixed naphthalene fractions, mineral
oils, substituted aromatic organic liquids such as dioctyl
phthalate; kerosene; dialkyl amides of various fatty acids,
particularly the dimethyl amides; and glycol ethers such as the
n-butyl ether, ethyl ether or methyl ether of diethylene glycol,
and the methyl ether of triethylene glycol and the like. Mixtures
of two or more organic liquids may also be employed in the
preparation of the emulsifiable concentrate. Surface-active
emulsifying agents are typically employed in liquid formulations
and in an amount of from 0.1 to 20 percent by weight based on the
combined weight of the emulsifying agents. The formulations can
also contain other compatible additives, for example, plant growth
regulators and other biologically active compounds used in
agriculture.
Aqueous suspensions comprise suspensions of one or more
water-insoluble pesticidally active ingredients dispersed in an
aqueous vehicle at a concentration in the range from about 5 to
about 50 weight percent, based on the total weight of the aqueous
suspension. Suspensions are prepared by finely grinding one or more
of the pesticidally active ingredients, and vigorously mixing the
ground material into a vehicle comprised of water and surfactants
chosen from the same types discussed above. Other components, such
as inorganic salts and synthetic or natural gums, may also be added
to increase the density and viscosity of the aqueous vehicle. It is
often most effective to grind and mix at the same time by preparing
the aqueous mixture and homogenizing it in an implement such as a
sand mill, ball mill, or piston-type homogenizer.
Aqueous emulsions comprise emulsions of one or more water-insoluble
pesticidally active ingredients emulsified in an aqueous vehicle at
a concentration typically in the range from about 5 to about 50
weight percent, based on the total weight of the aqueous emulsion.
If the pesticidally active ingredient is a solid it must be
dissolved in a suitable water-immiscible solvent prior to the
preparation of the aqueous emulsion. Emulsions are prepared by
emulsifying the liquid pesticidally active ingredient or
water-immiscible solution thereof into an aqueous medium typically
with inclusion of surfactants that aid in the formation and
stabilization of the emulsion as described above. This is often
accomplished with the aid of vigorous mixing provided by high shear
mixers or homogenizers.
The compositions of the present invention can also be granular
formulations, which are particularly useful for applications to the
soil. Granular formulations usually contain from about 0.5 to about
10 weight percent, based on the total weight of the granular
formulation of the pesticidally active ingredient(s), dispersed in
an inert carrier which consists entirely or in large part of
coarsely divided inert material such as attapulgite, bentonite,
diatomite, clay or a similar inexpensive substance. Such
formulations are usually prepared by dissolving the pesticidally
active ingredients in a suitable solvent and applying it to a
granular carrier which has been preformed to the appropriate
particle size, in the range of from about 0.5 to about 3 mm. A
suitable solvent is a solvent in which the compound is
substantially or completely soluble. Such formulations may also be
prepared by making a dough or paste of the carrier and the compound
and solvent, and crushing and drying to obtain the desired granular
particle.
Dusts can be prepared by intimately mixing one or more of the
pesticidally active ingredients in powdered form with a suitable
dusty agricultural carrier, such as, for example, kaolin clay,
ground volcanic rock, and the like. Dusts can suitably contain from
about 1 to about 10 weight percent of the compounds, based on the
total weight of the dust.
The formulations may additionally contain adjuvant surfactants to
enhance deposition, wetting and penetration of the pesticidally
active ingredients onto the target site such as a crop or organism.
These adjuvant surfactants may optionally be employed as a
component of the formulation or as a tank mix. The amount of
adjuvant surfactant will typically vary from 0.01 to 1.0 percent by
volume, based on a spray-volume of water, preferably 0.05 to 0.5
volume percent. Suitable adjuvant surfactants include, but are not
limited to ethoxylated nonyl phenols, ethoxylated synthetic or
natural alcohols, salts of the esters of sulfosuccinic acids,
ethoxylated organosilicones, ethoxylated fatty amines and blends of
surfactants with mineral or vegetable oils.
The formulations may optionally include combinations that contain
one or more other pesticidal compounds. Such additional pesticidal
compounds may be fungicides, insecticides, nematicides, miticides,
arthropodicides, bactericides or combinations thereof that are
compatible with the compounds of the present invention in the
medium selected for application, and not antagonistic to the
activity of the present compounds. Accordingly, in such
embodiments, the other pesticidal compound is employed as a
supplemental toxicant for the same or for a different pesticidal
use. The compounds of the present invention, and the pesticidal
compound in the combination can generally be present in a weight
ratio of from 1:100 to 100:1.
The compounds disclosed in this invention can be in the form of
pesticidally acceptable acid addition salts.
By way of non-limiting example, an amine function can form salts
with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic,
benzoic, citric, malonic, salicylic, malic, fumaric, oxalic,
succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic,
benzenesulfonic, methanesulfonic, ethanesulfonic,
hydroxymethanesulfonic, and hydroxyethanesulfonic acids.
Additionally, by way of non-limiting example, an acid function can
form salts including those derived from alkali or alkaline earth
metals and those derived from ammonia and amines. Examples of
preferred cations include sodium, potassium, magnesium, and aminium
cations.
The salts are prepared by contacting the free base form with a
sufficient amount of the desired acid to produce a salt. The free
base forms may be regenerated by treating the salt with a suitable
dilute aqueous base solution such as dilute aqueous NaOH, potassium
carbonate, ammonia, and sodium bicarbonate. As an example, in many
cases, a pesticide is modified to a more water soluble form e.g.
2,4-dichlorophenoxy acetic acid dimethyl amine salt is a more water
soluble form of 2,4-dichlorophenoxy acetic acid, a well known
herbicide.
The compounds disclosed in this invention can also form stable
complexes with solvent molecules that remain intact after the
non-complexed solvent molecules are removed from the compounds.
These complexes are often referred to as "solvates".
Certain compounds disclosed in this document can exist as one or
more stereoisomers. The various stereoisomers include geometric
isomers, diastereomers, and enantiomers. Thus, the compounds
disclosed in this invention include racemic mixtures, individual
stereoisomers, and optically active mixtures. It will be
appreciated by those skilled in the art that one stereoisomer may
be more active than the others. Individual stereoisomers and
optically active mixtures may be obtained by selective synthetic
procedures, by conventional synthetic procedures using resolved
starting materials, or by conventional resolution procedures.
The compounds of the present invention can also be combined with
other agricultural fungicides to form fungicidal mixtures and
synergistic mixtures thereof. The fungicidal compounds of the
present invention are often applied in conjunction with one or more
other fungicides to control a wider variety of undesirable
diseases. When used in conjunction with other fungicide(s), the
presently claimed compounds can be formulated with the other
fungicide(s), tank mixed with the other fungicide(s) or applied
sequentially with the other fungicide(s). Such other fungicides
include but are not limited to
2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,
8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin,
Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus
subtilis, benalaxyl, benomyl, benthiavalicarb-isopropyl,
benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl,
bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, Bordeaux
mixture, boscalid, bromuconazole, bupirimate, BYF 1047, calcium
polysulfide, captafol, captan, carbendazim, carboxin, carpropamid,
carvone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium
minitans, copper hydroxide, copper octanoate, copper oxychloride,
copper sulfate, copper sulfate (tribasic), cuprous oxide,
cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil,
coumarin, dazomet, debacarb, diammonium
ethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen,
diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole,
difenzoquat ion, diflumetorim, dimethomorph, dimoxystrobin,
diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine,
dithianon, dodemorph, dodemorph acetate, dodine, dodine free base,
edifenphos, enestrobin, epoxiconazole, ethaboxam, ethoxyquin,
etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole,
fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin,
fenpropimorph, fentin, fentin acetate, fentin hydroxide, ferbam,
ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide,
fluopyram, fluoroimide, fluoxastrobin, fluquinconazole,
flusilazole, flusulfamide, flutianil, flutolanil, flutriafol,
folpet, formaldehyde, fosetyl, fosetyl-aluminium, fuberidazole,
furalaxyl, furametpyr, guazatine, guazatine acetates, GY-81,
hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalil
sulfate, imibenconazole, iminoctadine, iminoctadine triacetate,
iminoctadine tris(albesilate), ipconazole, iprobenfos, iprodione,
iprovalicarb, isoprothiolane, isopyrazam, isotianil, kasugamycin,
kasugamycin hydrochloride hydrate, kresoxim-methyl, mancopper,
mancozeb, mandipropamid, maneb, mepanipyrim, mepronil, mercuric
chloride, mercuric oxide, mercurous chloride, metalaxyl, mefenoxam,
metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium,
metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate,
metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil,
nabam, nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic
acid (fatty acids), orysastrobin, oxadixyl, oxine-copper,
oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole,
pencycuron, pentachlorophenol, pentachlorophenyl laurate,
penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide,
picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium
bicarbonate, potassium hydroxyquinoline sulfate, probenazole,
prochloraz, procymidone, propamocarb, propamocarb hydrochloride,
propiconazole, propineb, proquinazid, prothioconazole,
pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos,
pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyroquilon,
quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis
extract, sedaxane, silthiofam, simeconazole, sodium
2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide,
spiroxamine, sulfur, SYP-Z071, SYP-Z048, tar oils, tebuconazole,
tebufloquin, tecnazene, tetraconazole, thiabendazole, thifluzamide,
thiophanate-methyl, thiram, tiadinil, tolclofos-methyl,
tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole,
tridemorph, trifloxystrobin, triflumizole, triforine,
triticonazole, validamycin, valifenalate, valiphenal, vinclozolin,
zineb, ziram, zoxamide, Candida oleophila, Fusarium oxysporum,
Gliocladium spp., Phlebiopsis gigantea, Streptomyces griseoviridis,
Trichoderma spp.,
(RS)-N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,
1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone
hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,
2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,
2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,
2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,
2-methoxyethylmercury silicate,
3-(4-chloro-phenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl
thiocyanateme, ampropylfos, anilazine, azithiram, barium
polysulfide, Bayer 32394, benodanil, benquinox, bentaluron,
benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,
bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate,
cadmium calcium copper zinc chromate sulfate, carbamorph, CECA,
chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox,
climbazole, copper bis(3-phenylsalicylate), copper zinc chromate,
cufraneb, cupric hydrazinium sulfate, cuprobam, cyclafuramid,
cypendazole, cyprofuram, decafentin, dichlone, dichlozoline,
diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon,
dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP,
etaconazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan,
fluotrimazole, furcarbanil, furconazole, furconazole-cis,
furmecyclox, furophanate, glyodine, griseofulvin, halacrinate,
Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaledione,
mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury
dicyandiamide, metsulfovax, milneb, mucochloric anhydride,
myclozolin, N-3,5-dichlorophenyl-succinimide,
N-3-nitrophenyl-itaconimide, natamycin,
N-ethylmercurio-4-toluenesulfonanilide, nickel
bis(dimethyldithiocarbamate), OCH, phenylmercury
dimethyldithiocarbamate, phenylmercury nitrate, phosdiphen,
prothiocarb; prothiocarb hydrochloride, pyracarbolid, pyridinitril,
pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid,
quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen,
tecoram, thiadifluor, thicyofen, thiochlorfenphim, thiophanate,
thioquinox, tioxymid, triamiphos, triarimol, triazbutil,
trichlamide, urbacid, XRD-563, and zarilamid, IK-1140, and any
combinations thereof.
Additionally, the compounds of the present invention can be
combined with other pesticides, including insecticides,
nematicides, miticides, arthropodicides, bactericides or
combinations thereof that are compatible with the compounds of the
present invention in the medium selected for application, and not
antagonistic to the activity of the present compounds to form
pesticidal mixtures and synergistic mixtures thereof. The
fungicidal compounds of the present invention are often applied in
conjunction with one or more other pesticides to control a wider
variety of undesirable pests. When used in conjunction with other
pesticides, the presently claimed compounds can be formulated with
the other pesticide(s), tank mixed with the other pesticide(s) or
applied sequentially with the other pesticide(s). Typical
insecticides include, but are not limited to: antibiotic
insecticides such as allosamidin and thuringiensin; macrocyclic
lactone insecticides such as spinosad and spinetoram; avermectin
insecticides such as abamectin, doramectin, emamectin,
eprinomectin, ivermectin and selamectin; milbemycin insecticides
such as lepimectin, milbemectin, milbemycin oxime and moxidectin;
arsenical insecticides such as calcium arsenate, copper
acetoarsenite, copper arsenate, lead arsenate, potassium arsenite
and sodium arsenite; botanical insecticides such as anabasine,
azadirachtin, d-limonene, nicotine, pyrethrins, cinerins, cinerin
I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II,
quassia, rotenone, ryania and sabadilla; carbamate insecticides
such as bendiocarb and carbaryl; benzofuranyl methylcarbamate
insecticides such as benfuracarb, carbofuran, carbosulfan,
decarbofuran and furathiocarb; dimethylcarbamate insecticides
dimitan, dimetilan, hyquincarb and pirimicarb; oxime carbamate
insecticides such as alanycarb, aldicarb, aldoxycarb, butocarboxim,
butoxycarboxim, methomyl, nitrilacarb, oxamyl, tazimcarb,
thiocarboxime, thiodicarb and thiofanox; phenyl methylcarbamate
insecticides such as allyxycarb, aminocarb, bufencarb, butacarb,
carbanolate, cloethocarb, dicresyl, dioxacarb, EMPC, ethiofencarb,
fenethacarb, fenobucarb, isoprocarb, methiocarb, metolcarb,
mexacarbate, promacyl, promecarb, propoxur, trimethacarb, XMC and
xylylcarb; diamide insecticides such as chlorantraniliprole,
cyantraniliprole and flubendiamide; dinitrophenol insecticides such
as dinex, dinoprop, dinosam and DNOC; fluorine insecticides such as
barium hexafluorosilicate, cryolite, sodium fluoride, sodium
hexafluorosilicate and sulfluramid; formamidine insecticides such
as amitraz, chlordimeform, formetanate and formparanate; fumigant
insecticides such as acrylonitrile, carbon disulfide, carbon
tetrachloride, chloroform, chloropicrin, para-dichlorobenzene,
1,2-dichloropropane, ethyl formate, ethylene dibromide, ethylene
dichloride, ethylene oxide, hydrogen cyanide, iodomethane, methyl
bromide, methylchloroform, methylene chloride, naphthalene,
phosphine, sulfuryl fluoride and tetrachloroethane; inorganic
insecticides such as borax, calcium polysulfide, copper oleate,
mercurous chloride, potassium thiocyanate and sodium thiocyanate;
chitin synthesis inhibitors such as bistrifluoron, buprofezin,
chlorfluazuron, cyromazine, diflubenzuron, flucycloxuron,
flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron,
penfluoron, teflubenzuron and triflumuron; juvenile hormone mimics
such as epofenonane, fenoxycarb, hydroprene, kinoprene, methoprene,
pyriproxyfen and triprene; juvenile hormones such as juvenile
hormone I, juvenile hormone II and juvenile hormone III; moulting
hormone agonists such as chromafenozide, halofenozide,
methoxyfenozide and tebufenozide; moulting hormones such as
.alpha.-ecdysone and ecdysterone; moulting inhibitors such as
diofenolan; precocenes such as precocene I, precocene II and
precocene III; unclassified insect growth regulators such as
dicyclanil; nereistoxin analogue insecticides such as bensultap,
cartap, thiocyclam and thiosultap; nicotinoid insecticides such as
flonicamid; nitroguanidine insecticides such as clothianidin,
dinotefuran, imidacloprid and thiamethoxam; nitromethylene
insecticides such as nitenpyram and nithiazine; pyridylmethyl-amine
insecticides such as acetamiprid, imidacloprid, nitenpyram and
thiacloprid; organochlorine insecticides such as bromo-DDT,
camphechlor, DDT, pp'-DDT, ethyl-DDD, HCH, gamma-HCH, lindane,
methoxychlor, pentachlorophenol and TDE; cyclodiene insecticides
such as aldrin, bromocyclen, chlorbicyclen, chlordane, chlordecone,
dieldrin, dilor, endosulfan, endrin, HEOD, heptachlor, HHDN,
isobenzan, isodrin, kelevan and mirex; organophosphate insecticides
such as bromfenvinfos, chlorfenvinphos, crotoxyphos, dichlorvos,
dicrotophos, dimethylvinphos, fospirate, heptenophos,
methocrotophos, mevinphos, monocrotophos, naled, naftalofos,
phosphamidon, propaphos, TEPP and tetrachlorvinphos;
organothiophosphate insecticides such as dioxabenzofos, fosmethilan
and phenthoate; aliphatic organothiophosphate insecticides such as
acethion, amiton, cadusafos, chlorethoxyfos, chlormephos,
demephion, demephion-O, demephion-S, demeton, demeton-O, demeton-S,
demeton-methyl, demeton-O-methyl, demeton-S-methyl,
demeton-S-methylsulphon, disulfoton, ethion, ethoprophos, IPSP,
isothioate, malathion, methacrifos, oxydemeton-methyl, oxydeprofos,
oxydisulfoton, phorate, sulfotep, terbufos and thiometon; aliphatic
amide organothiophosphate insecticides such as amidithion,
cyanthoate, dimethoate, ethoate-methyl, formothion, mecarbam,
omethoate, prothoate, sophamide and vamidothion; oxime
organothiophosphate insecticides such as chlorphoxim, phoxim and
phoxim-methyl; heterocyclic organothiophosphate insecticides such
as azamethiphos, coumaphos, coumithoate, dioxathion, endothion,
menazon, morphothion, phosalone, pyraclofos, pyridaphenthion and
quinothion; benzothiopyran organothiophosphate insecticides such as
dithicrofos and thicrofos; benzotriazine organothiophosphate
insecticides such as azinphos-ethyl and azinphos-methyl; isoindole
organothiophosphate insecticides such as dialifos and phosmet;
isoxazole organothiophosphate insecticides such as isoxathion and
zolaprofos; pyrazolopyrimidine organothiophosphate insecticides
such as chlorprazophos and pyrazophos; pyridine organothiophosphate
insecticides such as chlorpyrifos and chlorpyrifos-methyl;
pyrimidine organothiophosphate insecticides such as butathiofos,
diazinon, etrimfos, lirimfos, pirimiphos-ethyl, pirimiphos-methyl,
primidophos, pyrimitate and tebupirimfos; quinoxaline
organothiophosphate insecticides such as quinalphos and
quinalphos-methyl; thiadiazole organothiophosphate insecticides
such as athidathion, lythidathion, methidathion and prothidathion;
triazole organothiophosphate insecticides such as isazofos and
triazophos; phenyl organothiophosphate insecticides such as
azothoate, bromophos, bromophos-ethyl, carbophenothion,
chlorthiophos, cyanophos, cythioate, dicapthon, dichlofenthion,
etaphos, famphur, fenchlorphos, fenitrothion fensulfothion,
fenthion, fenthion-ethyl, heterophos, jodfenphos, mesulfenfos,
parathion, parathion-methyl, phenkapton, phosnichlor, profenofos,
prothiofos, sulprofos, temephos, trichlormetaphos-3 and trifenofos;
phosphonate insecticides such as butonate and trichlorfon;
phosphonothioate insecticides such as mecarphon; phenyl
ethylphosphonothioate insecticides such as fonofos and
trichloronat; phenyl phenylphosphonothioate insecticides such as
cyanofenphos, EPN and leptophos; phosphoramidate insecticides such
as crufomate, fenamiphos, fosthietan, mephosfolan, phosfolan and
pirimetaphos; phosphoramidothioate insecticides such as acephate,
isocarbophos, isofenphos, methamidophos and propetamphos;
phosphorodiamide insecticides such as dimefox, mazidox, mipafox and
schradan; oxadiazine insecticides such as indoxacarb; oxadiazolone
insecticides such as metoxadiazone; phthalimide insecticides such
as dialifos, phosmet and tetramethrin; pyrazole insecticides such
as acetoprole, cyenopyrafen, ethiprole, fipronil, pyrafluprole,
pyriprole, tebufenpyrad, tolfenpyrad and vaniliprole; pyrethroid
ester insecticides such as acrinathrin, allethrin, bioallethrin,
barthrin, bifenthrin, bioethanomethrin, cyclethrin, cycloprothrin,
cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin,
lambda-cyhalothrin, cypermethrin, alpha-cypermethrin,
beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin,
cyphenothrin, deltamethrin, dimefluthrin, dimethrin, empenthrin,
fenfluthrin, fenpirithrin, fenpropathrin, fenvalerate,
esfenvalerate, flucythrinate, fluvalinate, tau-fluvalinate,
furethrin, imiprothrin, metofluthrin, permethrin, biopermethrin,
transpermethrin, phenothrin, prallethrin, profluthrin,
pyresmethrin, resmethrin, bioresmethrin, cismethrin, tefluthrin,
terallethrin, tetramethrin, tralomethrin and transfluthrin;
pyrethroid ether insecticides such as etofenprox, flufenprox,
halfenprox, protrifenbute and silafluofen; pyrimidinamine
insecticides such as flufenerim and pyrimidifen; pyrrole
insecticides such as chlorfenapyr; tetramic acid insecticides such
as spirotetramat; tetronic acid insecticides such as spiromesifen;
thiourea insecticides such as diafenthiuron; urea insecticides such
as flucofuron and sulcofuron; and unclassified insecticides such as
closantel, copper naphthenate, crotamiton, EXD, fenazaflor,
fenoxacrim, hydramethylnon, isoprothiolane, malonoben,
metaflumizone, nifluridide, plifenate, pyridaben, pyridalyl,
pyrifluquinazon, rafoxanide, sulfoxaflor, triarathene, triazamate,
and any combinations thereof.
Additionally, the compounds of the present invention may be
combined with herbicides that are compatible with the compounds of
the present invention in the medium selected for application, and
not antagonistic to the activity of the present compounds to form
pesticidal mixtures and synergistic mixtures thereof. The
fungicidal compounds of the present disclosure may be applied in
conjunction with one or more herbicides to control a wide variety
of undesirable plants. When used in conjunction with herbicides,
the presently claimed compounds may be formulated with the
herbicide(s), tank mixed with the herbicide(s) or applied
sequentially with the herbicide(s). Typical herbicides include, but
are not limited to: amide herbicides such as allidochlor,
beflubutamid, benzadox, benzipram, bromobutide, cafenstrole, CDEA,
cyprazole, dimethenamid, dimethenamid-P, diphenamid, epronaz,
etnipromid, fentrazamide, flupoxam, fomesafen, halosafen,
isocarbamid, isoxaben, napropamide, naptalam, pethoxamid,
propyzamide, quinonamid and tebutam; anilide herbicides such as
chloranocryl, cisanilide, clomeprop, cypromid, diflufenican,
etobenzanid, fenasulam, flufenacet, flufenican, mefenacet,
mefluidide, metamifop, monalide, naproanilide, pentanochlor,
picolinafen and propanil; arylalanine herbicides such as
benzoylprop, flamprop and flamprop-M; chloroacetanilide herbicides
such as acetochlor, alachlor, butachlor, butenachlor, delachlor,
diethatyl, dimethachlor, metazachlor, metolachlor, S-metolachlor,
pretilachlor, propachlor, propisochlor, prynachlor, terbuchlor,
thenylchlor and xylachlor; sulfonanilide herbicides such as
benzofluor, perfluidone, pyrimisulfan and profluazol; sulfonamide
herbicides such as asulam, carbasulam, fenasulam and oryzalin;
thioamide herbicides such as chlorthiamid; antibiotic herbicides
such as bilanafos; benzoic acid herbicides such as chloramben,
dicamba, 2,3,6-TBA and tricamba; pyrimidinyloxybenzoic acid
herbicides such as bispyribac and pyriminobac;
pyrimidinylthiobenzoic acid herbicides such as pyrithiobac;
phthalic acid herbicides such as chlorthal; picolinic acid
herbicides such as aminopyralid, clopyralid and picloram;
quinolinecarboxylic acid herbicides such as quinclorac and
quinmerac; arsenical herbicides such as cacodylic acid, CMA, DSMA,
hexaflurate, MAA, MAMA, MSMA, potassium arsenite and sodium
arsenite; benzoylcyclohexanedione herbicides such as mesotrione,
sulcotrione, tefuryltrione and tembotrione; benzofuranyl
alkylsulfonate herbicides such as benfuresate and ethofumesate;
benzothiazole herbicides such as benzazolin; carbamate herbicides
such as asulam, carboxazole chlorprocarb, dichlormate, fenasulam,
karbutilate and terbucarb; carbanilate herbicides such as barban,
BCPC, carbasulam, carbetamide, CEPC, chlorbufam, chlorpropham,
CPPC, desmedipham, phenisopham, phenmedipham, phenmedipham-ethyl,
propham and swep; cyclohexene oxime herbicides such as alloxydim,
butroxydim, clethodim, cloproxydim, cycloxydim, profoxydim,
sethoxydim, tepraloxydim and tralkoxydim; cyclopropylisoxazole
herbicides such as isoxachlortole and isoxaflutole; dicarboximide
herbicides such as cinidon-ethyl, flumezin, flumiclorac,
flumioxazin and flumipropyn; dinitroaniline herbicides such as
benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin,
isopropalin, methalpropalin, nitralin, oryzalin, pendimethalin,
prodiamine, profluralin and trifluralin; dinitrophenol herbicides
such as dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC,
etinofen and medinoterb; diphenyl ether herbicides such as
ethoxyfen; nitrophenyl ether herbicides such as acifluorfen,
aclonifen, bifenox, chlomethoxyfen, chlornitrofen, etnipromid,
fluorodifen, fluoroglycofen, fluoronitrofen, fomesafen,
furyloxyfen, halosafen, lactofen, nitrofen, nitrofluorfen and
oxyfluorfen; dithiocarbamate herbicides such as dazomet and metam;
halogenated aliphatic herbicides such as alorac, chloropon,
dalapon, flupropanate, hexachloroacetone, iodomethane, methyl
bromide, monochloroacetic acid, SMA and TCA; imidazolinone
herbicides such as imazamethabenz, imazamox, imazapic, imazapyr,
imazaquin and imazethapyr; inorganic herbicides such as ammonium
sulfamate, borax, calcium chlorate, copper sulfate, ferrous
sulfate, potassium azide, potassium cyanate, sodium azide, sodium
chlorate and sulfuric acid; nitrile herbicides such as bromobonil,
bromoxynil, chloroxynil, dichlobenil, iodobonil, ioxynil and
pyraclonil; organophosphorus herbicides such as amiprofos-methyl,
anilofos, bensulide, bilanafos, butamifos, 2,4-DEP, DMPA, EBEP,
fosamine, glufosinate, glufosinate-P, glyphosate and piperophos;
phenoxy herbicides such as bromofenoxim, clomeprop, 2,4-DEB,
2,4-DEP, difenopenten, disul, erbon, etnipromid, fenteracol and
trifopsime; oxadiazoline herbicides such as methazole, oxadiargyl,
oxadiazon; oxazole herbicides such as fenoxasulfone; phenoxyacetic
herbicides such as 4-CPA, 2,4-D, 3,4-DA, MCPA, MCPA-thioethyl and
2,4,5-T; phenoxybutyric herbicides such as 4-CPB, 2,4-DB, 3,4-DB,
MCPB and 2,4,5-TB; phenoxypropionic herbicides such as cloprop,
4-CPP, dichlorprop, dichlorprop-P, 3,4-DP, fenoprop, mecopropand
mecoprop-P; aryloxyphenoxypropionic herbicides such as chlorazifop,
clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenoxaprop-P,
fenthiaprop, fluazifop, fluazifop-P, haloxyfop, haloxyfop-P,
isoxapyrifop, metamifop, propaquizafop, quizalofop, quizalofop-P
and trifop; phenylenediamine herbicides such as dinitramine and
prodiamine; pyrazole herbicides such as pyroxasulfone;
benzoylpyrazole herbicides such as benzofenap, pyrasulfotole,
pyrazolynate, pyrazoxyfen, and topramezone; phenylpyrazole
herbicides such as fluazolate, nipyraclofen, pioxaden and
pyraflufen; pyridazine herbicides such as credazine, pyridafol and
pyridate; pyridazinone herbicides such as brompyrazon, chloridazon,
dimidazon, flufenpyr, metflurazon, norflurazon, oxapyrazon and
pydanon; pyridine herbicides such as aminopyralid, cliodinate,
clopyralid, dithiopyr, fluoroxypyr, haloxydine, picloram,
picolinafen, pyriclor, thiazopyr and triclopyr; pyrimidinediamine
herbicides such as iprymidam and tioclorim; quaternary ammonium
herbicides such as cyperquat, diethamquat, difenzoquat, diquat,
morfamquat and paraquat; thiocarbamate herbicides such as butylate,
cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate,
methiobencarb, molinate, orbencarb, pebulate, prosulfocarb,
pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate and
vemolate; thiocarbonate herbicides such as dimexano, EXD and
proxan; thiourea herbicides such as methiuron; triazine herbicides
such as dipropetryn, indaziflam, triaziflam and trihydroxytriazine;
chlorotriazine herbicides such as atrazine, chlorazine, cyanazine,
cyprazine, eglinazine, ipazine, mesoprazine, procyazine,
proglinazine, propazine, sebuthylazine, simazine, terbuthylazine
and trietazine; methoxytriazine herbicides such as atraton,
methometon, prometon, secbumeton, simeton and terbumeton;
methylthiotriazine herbicides such as ametryn, aziprotryne,
cyanatryn, desmetryn, dimethametryn, methoprotryne, prometryn,
simetryn and terbutryn; triazinone herbicides such as ametridione,
amibuzin, hexazinone, isomethiozin, metamitron and metribuzin;
triazole herbicides such as amitrole, cafenstrole, epronaz and
flupoxam; triazolone herbicides such as amicarbazone, bencarbazone,
carfentrazone, flucarbazone, ipfencarbazone, propoxycarbazone,
sulfentrazone and thiencarbazone-methyl; triazolopyrimidine
herbicides such as cloransulam, diclosulam, florasulam,
flumetsulam, metosulam, penoxsulam and pyroxsulam; uracil
herbicides such as benzfendizone, bromacil, butafenacil,
flupropacil, isocil, lenacil, saflufenacil and terbacil; urea
herbicides such as benzthiazuron, cumyluron, cycluron,
dichloralurea, diflufenzopyr, isonoruron, isouron,
methabenzthiazuron, monisouron and noruron; phenylurea herbicides
such as anisuron, buturon, chlorbromuron, chloreturon,
chlorotoluron, chloroxuron, daimuron, difenoxuron, dimefuron,
diuron, fenuron, fluometuron, fluothiuron, isoproturon, linuron,
methiuron, methyldymron, metobenzuron, metobromuron, metoxuron,
monolinuron, monuron, neburon, parafluoron, phenobenzuron, siduron,
tetrafluoron and thidiazuron; pyrimidinylsulfonylurea herbicides
such as amidosulfuron, azimsulfuron, bensulfuron, chlorimuron,
cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron,
flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron,
mesosulfuron, metazosulfuron, nicosulfuron, orthosulfamuron,
oxasulfuron, primisulfuron, propyrisulfuron, pyrazosulfuron,
rimsulfuron, sulfometuron, sulfosulfuron and trifloxysulfuron;
triazinylsulfonylurea herbicides such as chlorsulfuron,
cinosulfuron, ethametsulfuron, iodosulfuron, metsulfuron,
prosulfuron, thifensulfuron, triasulfuron, tribenuron,
triflusulfuron and tritosulfuron; thiadiazolylurea herbicides such
as buthiuron, ethidimuron, tebuthiuron, thiazafluoron and
thidiazuron; and unclassified herbicides such as acrolein, allyl
alcohol, aminocyclopyrachlor, azafenidin, bentazone, benzobicyclon,
bicyclopyrone, buthidazole, calcium cyanamide, cambendichlor,
chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol,
cinmethylin, clomazone, CPMF, cresol, cyanamide,
ortho-dichlorobenzene, dimepiperate, endothal, fluoromidine,
fluridone, fluorochloridone, flurtamone, fluthiacet, indanofan,
methyl isothiocyanate, OCH, oxaziclomefone, pentachlorophenol,
pentoxazone, phenylmercury acetate, prosulfalin, pyribenzoxim,
pyriftalid, quinoclamine, rhodethanil, sulglycapin, thidiazimin,
tridiphane, trimeturon, tripropindan and tritac.
The compounds of the present invention may have broad ranges of
efficacy as fungicides and insecticides. The exact amount of the
active material to be applied is dependent not only on the specific
active material being applied, but also on the particular action
desired, the pathogen or pest to be controlled, and the stage of
growth thereof, as well as the part of the plant, animal or other
medium to be contacted with the compound. Thus, all the compounds,
and formulations containing the same, may not be equally effective
at similar concentrations or against the same pathogen and pest
species.
The compounds are effective in use with plants in a phytologically
acceptable amount. The term "phytologically acceptable amount"
refers to an amount of a compound that kills or inhibits the pest
or plant disease for which control is desired, but is not
significantly toxic to the plant. This amount will generally be
from about 0.1 to about 1000 ppm (parts per million), with 1 to 500
ppm being preferred.
The exact concentration of compound required varies with the pest
or disease to be controlled, the type of formulation employed, the
method of application, the particular plant or animal species,
climate conditions, and the like. For fungicides, dilution and rate
of application will depend upon the type of equipment employed, the
method and frequency of application desired and diseases to be
controlled, but the effective amount is usually from about 0.01
kilogram (kg) to about 20 kg, of active ingredient (a.i.) per
hectare (ha). As a foliar fungicide, a compound of the present
invention is usually applied to growing plants at a rate of about
0.1 to about 5 and preferably from about 0.125 to about 0.5 kg per
hectare.
As a seed-applied fungicide, the amount of toxicant coated on the
seed is usually at a dosage rate of about 0.1 to about 250 grams
(g) and preferably from about 1 to about 60 g per 100 kilograms of
seed. As a soil fungicide, the chemical can be incorporated in the
soil or applied to the surface of the soil or a rice nursery box
usually at a rate of about 0.1 to about 5 kg per hectare.
The actual amount of insecticide or miticide to be applied to loci
of pests is generally not critical and can readily be determined by
those skilled in the art. In general, concentrations from about
0.01 grams of pesticide per hectare to about 5000 grams of
pesticide per hectare are expected to provide good control.
The locus to which a pesticide is applied can be any locus
inhabited by an pest, for example, vegetable crops, fruit and nut
trees, grape vines, ornamental plants, domesticated animals, the
interior or exterior surfaces of buildings, and the soil around
buildings. Controlling pests generally means that pest populations,
activity, or both, are reduced in a locus. This can come about
when: pest populations are repulsed from a locus; when pests are
incapacitated, partially or completely, temporarily or permanently,
in or around a locus; or pests are exterminated, in whole or in
part, in or around a locus. Of course a combination of these
results can occur. Generally, pest populations, activity, or both
are desirably reduce more than fifty percent, preferably more than
90 percent, even more preferably 99 percent.
Generally, with baits, the baits are placed in the ground where,
for example, termites can come into contact with the bait. Baits
can also be applied to a surface of a building, (horizontal,
vertical, or slant, surface) where, for example, ants, termites,
cockroaches, and flies, can come into contact with the bait.
Because of the unique ability of the eggs of some pests to resist
pesticides repeated applications may be desirable to control newly
emerged larvae.
Systemic movement of pesticides in plants may be utilized to
control pests on one portion of the plant by applying the
pesticides to a different portion of the plant, or to a location
where the root system of a plant can uptake pesticides. For
example, control of foliar-feeding insects can be controlled by
drip irrigation or furrow application, or by treating the seed
before planting. Seed treatment can be applied to all types of
seeds, including those from which plants genetically transformed to
express specialized traits will germinate. Representative examples
include those expressing proteins toxic to invertebrate pests, such
as Bacillus thuringiensis or other insecticidal toxins, those
expressing herbicide resistance, such as "Roundup Ready" seed, or
those with "stacked" foreign genes expressing insecticidal toxins,
herbicide resistance, nutrition-enhancement or any other beneficial
traits. Furthermore, such seed treatments with the invention
disclosed in this document can further enhance the ability of a
plant to better withstand stressful growing conditions. This
results in a healthier, more vigorous plant, which can lead to
higher yields at harvest time.
It should be readily apparent that the invention may be used with
plants genetically transformed to express specialized traits, such
as Bacillus thuringiensis or other insecticidal toxins, or those
expressing herbicide resistance, or those with "stacked" foreign
genes expressing insecticidal toxins, herbicide resistance,
nutrition-enhancement or any other beneficial traits. An example of
such a use is spraying such plants with the invention disclosed in
this document.
The invention disclosed in this document may be suitable for
controlling endoparasites and ectoparasites in the veterinary
medicine sector or in the field of animal keeping. Compounds
according to the invention are applied here in a known manner, such
as by oral administration in the form of, for example, tablets,
capsules, drinks, granules, by dermal application in the form of,
for example, dipping, spraying, pouring on, spotting on, and
dusting, and by parenteral administration in the form of, for
example, an injection.
The invention disclosed in this document may also be employed
advantageously in livestock keeping, for example, cattle, sheep,
pigs, chickens, and geese. Suitable formulations may be
administered orally to the animals with the drinking water or feed.
The dosages and formulations that are suitable depend on the
species.
In particular, the compounds of the present invention may
effectively control a variety of undesirable insects and fungi that
infect useful plant crops. Activity may be demonstrated for a
variety of fungi, including those causing following the following
plant diseases: Anthracnose of Cucumber (Colletotrichum
lagenarium); Powdery Mildew of Cucumber (Eysiphe spp.); Glume
Blotch of Wheat (Septoria nodorum); Downy Mildew of Cucumber
(Pseudoperonospora cubensis); Rice Blast (Magnaporthe grisea);
Brown Rust of Wheat (Puccinia recondita tritici); Stripe rust of
wheat (Puccinia striiformis); Soybean rust (Phakopspora
pachyrhizi); Septoria Blotch of Wheat (Septoria tritici); Apple
scab (Venturia inaequalis); Downy mildew of grape (Plasmopara
viticola); Powdery mildew of barley (Erysiphe hordei); Powdery
mildew of wheat (Erysiphe graminis); Powdery mildew of grape
(Uncinula necator); Late blight (Phytophthora infestans); Early
blight (Alternaria solani); Peanut leaf spot (Cercospora
arachidicola); Net blotch of barley (Pyrenophora teres); Barley
scald (Rhynchosporium secalis); Spot blotch of cereals
(Cochliobolus sativus); and Maize smut (Ustilago maydis).
Activity may be demonstrated by these compounds on a variety of
insects, including Beet Armyworm (Spodoptera exigua), Mosquito
(Aedes aegypti), Colorado Potato Beetle (Leptinotarsa
decemlineata). Fruit Fly (Drosophila melanogaster), Green peach
aphid (Myzus persicae), Cotton aphid (Aphis gossypii), and
Bollworm/corn earworm (Helicoverpa zea).
It will be understood by those in the art that the efficacy of the
compound on the foregoing fungi and insects establishes the general
utility of the compounds as fungicides and insecticides.
PREPARATION 1
##STR00026##
2-(4-Methoxy-2-methylphenyl)-ethylamine hydrochloride
4-Methoxy-2-methylphenylacetonitrile (3.0 g, 18.6 mmol) was
dissolved in 2B ethanol (65 mL). To the solution was added con. HCl
(2.4 mL) and 10% Pd/C (300 mg). The suspension was deaerated in a
500 mL Parr hydrogenation bottle and then pressurized with 55 psi
H.sub.2, and shaken. After 20 h, the reaction was recharged with
hydrogen and 10% Pd/C. After a total of 96 h, the reaction mixture
was filtered through Celite and the filtrate was concentrated in
vacuo. The off-white solid residue was recrystallized from
isopropanol and collected by suction filtration to afford 1.86 g
(50% yield) 2-(4-methoxy-2-methylphenyl)-ethylamine hydrochloride
as a white solid, melting point (M.P.) 220-222.degree. C. (gradual
softening and discoloration from 104-220.degree. C.). The filtrate
was concentrated in vacuo and the residue was washed with ethyl
acetate and filtered, providing an additional 1.34 g for a total
yield of 3.2 g (85% yield). GC/MS: m/z 165; .sup.1H NMR (DMSO) 8.25
(bs, 3H), 7.09 (d, 1H), 6.75 (m, 2H), 3.71 (s, 3H), 2.87 (m, 4H),
2.27 (s, 3H).
PREPARATION 2
##STR00027##
2-Amino-3,6-difluorobenzonitrile
2,3,6-Trifluorobenzonitrile (15 g) in ammonium hydroxide solution
(28% in water; 80 mL) and acetonitrile (40 mL) was stirred at
70.degree. C. in a pressure vessel for 16 h and the reaction was
complete based on GC-MS. Acetonitrile was removed under reduced
pressure, and water was added. The white solid precipitate was
suction filtered, washed with water and dried under house vacuum
over a weekend at room temperature to give 13.7 g (93%) of the
crude product; M.P. 90-92.degree. C. GC/MS: m/z 154. .sup.1H NMR
(CDCl.sub.3): .delta. 7.07-7.16 (m, 1H), 6.36-6.43 (m, 1H), 4.65
(br s, 2H).
2-Amino-3,5,6-trifluorobenzonitrile was prepared in the same way,
from 2,3,5,6-tetrafluorobenzonitrile (81% yield). GC/MS: m/z 172;
.sup.1H NMR (CDCl.sub.3): .delta. 7.13 (m, 1H), 4.47 (br s, 2H);
M.P. 112-115.degree..
PREPARATION 3
##STR00028##
N'-(2-Cyano-3,6-difluorophenyl)-N,N-dimethylformamidine
A solution of 2-amino-3,6-difluorobenzonitrile (1.92 g, 12.5 mmol)
and N,N-dimethylformamide dimethyl acetal (2.2 mL, 1.3 mmol) in 15
mL of toluene was heated to reflux for 1 h. The reaction was
complete based on GC-MS. The solvent was removed in vacuo and the
oily residue was suspended in hexane and a small amount of ether.
The mixture was then cooled in a freezer for 20 min. The resulting
solid was suction filtered, washed with hexane and dried to give
2.17 g (83% yield) of the product as a tan solid, M.P.
56-60.degree.; GC/MS: m/z 209. .sup.1H NMR (CDCl.sub.3): .delta.
7.86 (s, 1H), 7.16 (m, 1H), 6.63 (m, 1H), 3.12 (s, 3H), 3.10 (s,
3H).
N'-(2-Cyano-3,4,6-trifluorophenyl)-N,N-dimethylformamidine was
prepared in the same way, as a mixture of geometric isomers, from
2-amino-3,5,6-trifluorobenzonitrile (93% yield). .sup.1H NMR
(CDCl.sub.3): .delta. 7.80 (2s, integrate to 1H), 7.07-7.27 (m,
1H), 3.10 and 3.09 (2s, integrate to 6H); M.P. 83-86.degree..
PREPARATION 4
##STR00029##
(5,8-Difluoroquinazolin-4-yl)-[2-(4-methoxy-3-methylphenyl)-ethyl]-amine
N'-(2-Cyano-3,6-difluorophenyl)-N,N-dimethylformamidine (1.65 g,
7.9 mmol) and 3-methyl-4-methoxyphenethylamine hydrochloride (2.4
g, 11.8 mmol) were combined in acetic acid (2.55 mL) and absolute
ethanol (15 mL) and heated to reflux for 16 h. Upon cooling, the
solvent was removed under reduced pressure and the remaining solid
was slurried with water, suction filtered and washed with water,
dried in vacuum at 45.degree. C. to give 1.51 g (58%) of
(5,8-difluoroquinazolin-4-yl)-[2-(4-methoxy-3-methylphenyl)-ethyl]-amine
as an off-white solid. LC/MS: 330.18 (M.sup.++1). .sup.1H NMR
(CDCl.sub.3): .delta. 8.67 (s, 1H), 7.35 (m, 1H), 6.94-7.09 (m,
3H), 6.79 (d, J=9.0 Hz, 1H), 6.65-6.80 (br, 1H), 3.87 (q, J=6.9 Hz,
2H), 3.83 (s, 3H), 2.93 (t, J=6.9 Hz, 2H), 2.22 (s, 3H). M.P.
162-169.degree. C.
PREPARATION 5
##STR00030##
4-[2-(5,8-Difluoroquinazolin-4-ylamino)-ethyl]-2-methylphenol
To a solution of
(5,8-difluoroquinazolin-4-yl)-[2-(4-methoxy-3-methylphenyl)-ethyl]-amine
(0.86 g, 2.6 mmol) in CH.sub.2Cl.sub.2 (10 mL) cooled to
-50.degree. C., was added 7.8 mL BBr.sub.3 (1 M in
CH.sub.2Cl.sub.2, 7.8 mmol). The solution was allowed to warm to
room temperature and stirred overnight, and then quenched slowly
with methanol. The solvent was removed by rotary evaporation, and
the residue was diluted with water and stirred for a few min. The
pale yellow solid precipitate was collected by suction filtration,
washed with water, and dried in vacuum at 50.degree. C. overnight
to give 0.83 g (quantitative yield) of
4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methylphenol.
.sup.1H NMR (d.sub.4-DMSO+d.sub.6-acetone): .delta. 9.5-8.5 (m,
3H), 7.97 (m, 1H), 7.61 (m, 1H), 6.99 (s, 1H), 6.91 (d, J=8.1 Hz,
1H), 6.75 (d, J=8.1 Hz, 1H), 3.92 (m, 2H), 2.88 (t, J=7.8 Hz, 2H),
2.11 (s, 3H). LC/MS: 316.04 (M.sup.++1). The product was used in
the following reaction without further purification. M.P.
244-251.degree. C.
EXAMPLE 1
##STR00031##
(5,8-Difluoroquinazolin-4-yl)-{2-[3-methyl-4-(4-trifluoromethylpyridin-2-y-
loxy)-phenyl]-ethyl}-amine
A mixture of
4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methylphenol (0.47
g, 1.5 mmol), 2-fluoro-4-trifluoromethylpyridine (0.371 g, 2.25
mmol), and potassium carbonate (0.31 g, 2.25 mmol) in DMSO (7 mL)
was heated at 90.degree. C. overnight. The reaction was complete,
as determined by LC-MS. After cooling to room temperature, water
was added and the mixture was stirred for 10 min. The solid
precipitate was collected by filtration, washed with water, and
dried under vacuum at 50.degree. C. to provide 0.533 g (77%) of
(5,8-difluoroquinazolin-4-yl)-{2-[3-methyl-4-(4-trifluoromethylpyridin-2--
yloxy)-phenyl]-ethyl}-amine as an off-white solid, M.P.
108-110.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 8.69 (s, 1H),
8.31 (d, J=5.1 Hz, 1H), 7.34 (m, 1H), 7.13-7.21 (m, 4H), 6.96-7.03
(m, 2H), 6.71-6.84 (br, 1H), 3.94 (m, 2H), 3.02 (t, J=6.9 Hz, 2H),
2.17 (s, 3H). LC/MS: 461.13 (M.sup.++1).
PREPARATION 6
##STR00032##
4-[2-(5,8-Difluoroquinazolin-4-ylamino)-ethyl]-phenol
A mixture of tyramine (2.62 g, 19 mmol),
N'-(2-cyano-3,6-difluorophenyl)-N,N-dimethylformamidine (2.0 g,
9.56 mmol), acetic acid (3.4 mL, 60 mmol) and ethanol (50 mL) was
heated at 75.degree. C. for 16 h. Upon cooling, the solvent was
removed under reduced pressure and the remaining solid was stirred
in water for a few minutes, collected by suction filtration and
washed with water. The filter cake was dried under vacuum to give
2.25 g (78%) of
4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-phenol as an
off-white solid, M.P. 221-222.degree. C. .sup.1H NMR
(d.sub.6-DMSO): .delta. 9.16 (s, 1H), 8.53 (s, 1H), 7.73 (m, 1H),
7.59 (m, 1H), 7.52 (m, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.4
Hz, 2H), 3.74 (q, J=7.8, 5.7 Hz, 2H), 2.84 (t, J=7.8 Hz, 2H).
LC/MS: 302.04 (M.sup.++1).
EXAMPLE 2
##STR00033##
(5,8-Difluoroquinazolin-4-yl)-{2-[3-methoxy-4-(5-trifluoromethylpyridin-2--
yloxy)-phenyl]-ethyl}-amine
To a solution of
4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methoxyphenol
(3.73 g, 11.25 mmol) in DMF (25 mL) in a dry 250 mL round bottom
flask equipped with a dry nitrogen line and a magnetic stir bar was
added sodium hydride (324 mg, 13.5 mmol). After gas evolution had
subsided, 2-fluoro-5-trifluoromethyl-pyridine (2.05 g, 12.3 mmol)
was added, and the reaction mixture was stirred at 25.degree. C.
After 20 h, additional sodium hydride (50 mg, 2.1 mmol) and
2-fluoro-5-trifluoromethyl-pyridine (100 mg, 0.6 mmol) were added.
After 20 min, the reaction mixture was quenched by addition of sat.
aq. NH.sub.4Cl (30 mL) and concentrated in vacuo. The residue was
suspended in water (50 mL) and stirred vigorously to break up
chunks. The solid product was collected by suction filtration and
washed on the filter with water. The filter cake again was
suspended in water (50 mL) and stirred vigorously to break up
chunks. The solid product was collected by suction filtration and
washed with water. The filter cake was dried with suction on the
filter overnight to provide 5.26 g (98% yield) of
(5,8-difluoroquinazolin-4-yl)-{2-[3-methoxy-4-(5-trifluoromethylpyridin-2-
-yloxy)-phenyl]-ethyl}-amine as an off-white powder, M.P.
119-121.degree. C. LC-MS: 477 (M.sup.++1); .sup.1H NMR
(CDCl.sub.3): .delta. 8.69 (s, 1H), 8.4 (m, 1H), 7.89 (dd, 1H),
7.36 (m, 1H), 7.12 (m, 1H), 7.01 (m, 2H), 6.93 (m, 2H), 6.78 (bd,
1H), 3.97 (m, 2H), 3.75 (s, 3H), 3.06 (m, 2H).
PREPARATION 7
##STR00034##
2-Chloro-4-trifluoromethylpyridine N-oxide
To a solution of 2-chloro-4-trifluoromethylpyridine (1.81 g, 10
mmol) in trifluoroacetic acid (12 mL) was added 30% hydrogen
peroxide (8 mL), and the mixture was stirred at 50.degree. C. over
a weekend. The reaction mixture was poured into ice-cold water,
neutralized with solid Na.sub.2CO.sub.3 with stirring, and
extracted with ethyl acetate three times. The combined organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered,
concentrated, and dried to give 1.67 g of analytically pure
2-chloro-4-trifluoromethylpyridine N-oxide as a brown oil. .sup.1H
NMR (CDCl.sub.3): .delta. 8.45 (d, J=6.9 Hz, 1H), 7.77 (d, J=2.4
Hz, 1H), 7.47 (dd, J=6.9, 2.4 Hz, 1H). GC/MS: 197 [M].sup.+.
EXAMPLE 3
##STR00035##
(5,8-Difluoroquinazolin-4-yl)-{2-[3-methyl-4-(1-oxy-4-trifluoromethylpyrid-
in-2-yloxy)-phenyl]-ethyl}-amine
A mixture of
4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methylphenol,
(0.315 g, 1.0 mmol), 2-chloro-4-trifluoromethylpyridine N-oxide
(0.20 g, 1.1 mmol) and potassium carbonate (0.207 g, 1.5 mmol) in
DMSO (12 mL) was heated at 85.degree. C. with microwave irradiation
for 3 h. Water was added and the mixture was extracted with
CH.sub.2Cl.sub.2. The pooled organic fraction was washed with
brine, dried with Na.sub.2SO.sub.4, filtered, concentrated in
vacuo, passed through a silica gel plug, and further eluted with
EtOAc. The organic fractions were pooled and concentrated in vacuo
to give 0.326 g of the product as a yellow gum. The product was
redissolved in CH.sub.2Cl.sub.2 and washed with water to remove
DMSO, dried with Na.sub.2SO.sub.4, filtered, and concentrated to
give 0.286 g (60%) of
(5,8-difluoroquinazolin-4-yl)-{2-[3-methyl-4-(1-oxy-4-trifluorom-
ethylpyridin-2-yloxy)-phenyl]-ethyl}-amine
(5,8-difluoroquinazolin-4-yl)-{2-[3-methyl-4-(1-oxy-4-trifluoromethylpyri-
din-2-yloxy)-phenyl]-ethyl}-amine as a yellow solid, M.P.
140-150.degree.; MS m/z 476. .sup.1H NMR (CDCl.sub.3): .delta. 8.67
(s, 1H), 8.42 (d, J=6.6 Hz, 1H), 7.34 (m, 1H), 7.21-7.24 (m, 2H),
7.14-7.18 (m, 1H), 6.94-7.03 (m, 2H), 6.80 (d, J=2.4 Hz, 1H),
6.62-6.75 (br, 1H), 3.94 (q, J=7.2 Hz, 2H), 3.03 (t, J=7.2 Hz, 2H),
2.23 (s, 3H).
EXAMPLE 4
##STR00036##
5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-
-2-yloxy)-phenol
To a solution of
(5,8-difluoroquinazolin-4-yl)-{2-[3-methoxy-4-(4-trifluoromethylpyridin-2-
-yloxy)-phenyl]-ethyl}-amine (2.71 g, 5.69 mmol) in
CH.sub.2Cl.sub.2 (25 mL) cooled to -50.degree. C., was added 1 M
BBr.sub.3 in CH.sub.2Cl.sub.2 (17 mL, 17 mmol). The solution was
allowed to warm to room temperature and stirred overnight, and then
quenched slowly with methanol. The solvent was removed by rotary
evaporation and the residue was suspended in chloroform. The
product was collected by suction filtration to give 2.70 g
(quantitative) of
5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridi-
n-2-yloxy)-phenol. The product was used in the following reaction
without further purification. .sup.1H NMR (CD.sub.3OD): .delta.
8.78 (s, 1H), 8.39 (d, J=5.4 Hz, 1H), 7.93 (m, 1H), 7.54 (m, 1H),
7.45 (d, J=5.4 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.96
(d, J=2.1 Hz, 1H) 6.87 (dd, J=7.8, 2.1 Hz, 1H), 4.12 (t, J=7.5 Hz,
2H), 3.05 (t, J=7.5 Hz, 2H). LC/MS: 460.97 (M.sup.+-1).
EXAMPLE 5
##STR00037##
(5,8-Difluoroquinazolin-4-yl)-{2-[3-propoxy-4-(4-trifluoromethylpyridin-2--
yloxy)-phenyl]-ethyl}-amine
To a solution of
5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridi-
n-2-yloxy)-phenol (0.462 g, 0.5 mmol) in DMSO (5 mL) was added
1-iodopropane (0.204 g, 1.2 mmol) and K.sub.2CO.sub.3 (0.207 g, 1.5
mmol). The reaction mixture was stirred at 50.degree. C. overnight
and then at 70.degree. C. for another 24 h. After cooling to room
temperature, the mixture was poured into water and the gum-like
material was separated via suction filtration and washed with
water. The gum-like product then was partitioned between
CH.sub.2Cl.sub.2 and brine. The organic phase was dried over sodium
sulfate and concentrated in vacuo, and the product was purified by
preparative reverse phase HPLC to give 0.161 g (32%) of
(5,8-difluoroquinazolin-4-yl)-{2-[3-propoxy-4-(4-trifluoromethylpyridin-2-
-yloxy)-phenyl]-ethyl}-amine as a brown gum; MS m/z 504. .sup.1H
NMR (CDCl.sub.3): .delta. 8.68 (s, 1H), 8.26 (d, J=4.8 Hz, 1H),
7.33 (m, 1H), 7.08-7.15 (m, 3H), 6.87-7.03 (m, 3H), 6.70-6.83 (br,
1H), 3.89-3.97 (m, 2H), 3.80-3.86 (m, 2H), 3.02 (t, J=6.9 Hz, 2H),
1.51 (m, 2H), 0.66 (t, J=7.2 Hz, 3H). LC/MS: 506.10
(M.sup.++1).
PREPARATION 8
##STR00038##
2-Fluoro-4-methoxy-1-((E)-2-nitrovinyl)benzene
A solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 33 mmol) and
ammonium acetate (1.0 g, 13 mmol) in nitromethane (40 mL) was
heated on a steam bath for 2.5 h. The reaction mixture was
concentrated under reduced pressure, and the sticky residue was
partitioned between dichloromethane and water. The organic layer
was washed with half-saturated brine, dried (MgSO4), filtered, and
concentrated. The residue was triturated in hexane and the solid
was filtered and washed with hexane and dried to give 5.57 g of
crude product 2-fluoro-4-methoxy-1-((E)-2-nitrovinyl)benzene as an
orange solid, M.P. 80-82.degree. C. .sup.1H NMR (CDCl.sub.3):
.delta. 8.02 (d, J=13.5 Hz, 1H), 7.66 (d, J=13.5 Hz, 1H), 7.43 (m,
1H), 6.68-6.80 (m, 2H), 3.87 (s, 3H). GC/MS: 197 [M].sup.+.
2-(2-Fluoro-4-methoxyphenyl)ethylamine hydrochloride
Under a nitrogen atmosphere,
2-fluoro-4-methoxy-1-((E)-2-nitrovinyl)benzene (26.5 g, 134.5 mmol)
was added in portions to a suspension of LiAlH.sub.4 (16 g, 195
mmol) in THF (1 L) at 0.degree. C. The mixture then was heated at
reflux, and after 3.5 h, the reaction was complete as indicated by
GC. The mixture was cooled to 0.degree. C. and quenched carefully
with water (34.6 mL) and 10% aqueous NaOH (28 mL). After removal of
green precipitates by suction filtration, the filtrate was dried
over MgSO.sub.4, filtered and evaporated under reduced pressure.
The oily residue was dissolved in EtOAc (150 mL) and then conc. HCl
was added until pH reached 1, to form the hydrochloride salt. Ether
was added (1 L) with stirring and the solid was collected by
suction filtration and washed with a small amount of acetone, then
dried under vacuum to give 2-(2-fluoro-4-methoxyphenyl)ethylamine
hydrochloride as a white solid weighing 12.3 g, M.P.
162-165.degree. C. The filtrate was concentrated under reduced
pressure. Toluene was added and evaporated to azeotropically remove
the remaining water. The residue was dissolved in MeOH, and EtOAc
was added to precipitate the product which was filtered and washed
with ethyl acetate, affording another 7.3 g of product. The total
yield was 19.6 g (72%). .sup.1H NMR (CDCl.sub.3): .delta. 8.29 (br,
3H), 7.24 (t, J=8.7 Hz, 1H), 6.73-6.84 (m, 2H), 3.74 (s, 3H),
2.83-2.99 (m, 4H). LC/MS: 169.9 [M].sup.+-HCl.
EXAMPLE 6
##STR00039##
5-[2-(5,8-Difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-
-2-yloxy)-benzonitrile
A suspension of
{2-[3-bromo-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-(5,8-difl-
uoroquinazolin-4-yl)-amine) (137 mg, 0.26 mmol), CuCN (164 mg, 1.83
mmol) and DMF (10 mL) was heated at 126.degree. for 3 h, then
heated at reflux overnight. After addition of more CuCN (100 mg),
the reaction was heated at reflux 2 h, then concentrated in vacuo.
The residue was partitioned between water (10 mL) and EtOAc (10
mL). The aqueous layer was extracted with EtOAc (2.times.10 mL) and
the pooled organic fractions were dried (Na.sub.2SO.sub.4),
filtered through a silica gel/Celite plug and concentrated in vacuo
to provide
5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridi-
n-2-yloxy)-benzonitrile (70 mg) as an off-white powder (94% purity
by LC), 57% yield, M.P. 157-159.degree.. .sup.1H NMR (CDCl.sub.3):
.delta. 8.7 (bs, 1H), 8.29 (d, 1H), 7.62 (d, 1H), 7.57 (dd, 1H),
7.38 (m, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 7.26 (m, 1H), 7.04 (m,
1H), 6.76 (bm, 1H), 3.96 (m, 2H), 3.10 (t, 2H). MS: m/z 471.
EXAMPLE 7
##STR00040##
(5,8-Difluoroquinazolin-4-yl)-{2-[4-(4-trifluoromethylpyridin-2-yloxy)-3-v-
inylphenyl]-ethyl}-amine
{2-[3-Bromo-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-(5,8-difl-
uoroquinazolin-4-yl)-amine (890 mg, 1.7 mmol), vinyl tri-n-butyltin
(591 mg, 544 .mu.L, 1.9 mmol), 1,4-bis(diphenylphosphino)butane
(145 mg, 0.3 mmol), 2,6-di-tert-butyl-4-methylphenol (75 mg, 0.3
mmol) and Pd(OAc).sub.2 (49 mg, 0.22 mmol) were added to a Carousel
reactor tube containing toluene (5 mL) and fitted with a magnetic
stir bar and a dry nitrogen gas line. The reaction mixture was
heated to reflux. After 20 h, more Pd(OAc).sub.2 (49 mg, 0.22 mmol)
was added, and heating was continued. After another 20 h, the
reaction was cooled. The reaction mixture was washed sequentially
with water and brine, then dried (Na.sub.2SO.sub.4), filtered
through a silica gel and Celite plug, and concentrated in vacuo.
The residue was partitioned between acetonitrile (30 mL) and
pentane (5.times.20 mL). The acetonitrile fraction then was
purified by normal phase chromatography (silica gel with ethyl
acetate/cyclohexane eluent) and reverse phase chromatography (C-18
solid phase with acetonitrile/water eluent, 0.5% H.sub.3PO.sub.4)
to provide
(5,8-difluoroquinazolin-4-yl)-{2-[4-(4-trifluoromethylpyridin-2-yloxy)-3--
vinylphenyl]-ethyl}-amine as a white powder (375 mg), M.P.
86.degree.. .sup.1H NMR (CDCl.sub.3): .delta. 8.7 (s, 1H), 8.31 (d,
1H), 7.54 (d, 1H), 7.35 (m, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 7.14
(s, 1H), 7.06 (d, 1H), 6.78 (bm, 2H), 5.76 (d, 1H), 5.26 (d, 1H),
3.97 (m, 2H), 3.07 (t, 2H). MS: m/z 472.
EXAMPLE 8
##STR00041##
(5,8-Difluoroquinazolin-4-yl)-{2-[3-ethyl-4-(4-trifluoromethylpyridin-2-yl-
oxy)-phenyl]-ethyl}-amine
(5,8-Difluoroquinazolin-4-yl)-{2-[4-(4-trifluoromethyl-pyridin-2-yloxy)-3-
-vinylphenyl]-ethyl}-amine (250 mg), 10% Pd--C (100 mg) and ethyl
acetate (10 mL) were added to a 230 mL Corning shaker bottle filled
with nitrogen gas. The bottle was evacuated, then charged with
hydrogen (55 psi starting pressure) and shaken overnight. The
reaction mixture was filtered through Celite, and concentrated in
vacuo. The residue was purified by reverse phase chromatography
(C-18 solid phase with acetonitrile/water eluent, 0.5%
H.sub.3PO.sub.4) to provide
(5,8-difluoroquinazolin-4-yl)-{2-[3-ethyl-4-(4-trifluoromethylpyridin-2-y-
loxy)-phenyl]-ethyl}-amine as a white powder (77 mg), M.P.
121-122.degree.. .sup.1H NMR (CDCl.sub.3): .delta. 8.69 (s, 1H),
8.31 (d, 1H), 7.36 (m, 1H), 7.22 (m, 1H), 7.17 (m, 2H), 7.13 (s,
1H), 7.00 (m, 2H), 6.76 (bm, 1H), 3.95 (m, 2H), 3.04 (t, 2H), 2.55
(q, 2H), 1.16 (t, 3H). MS: m/z 474.
PREPARATION 9
##STR00042##
2-Chloro-4-(1,1-difluoroethyl)-pyridine
To a solution of 2-chloro-4-acetylpyridine (2.6 g, 17.2 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was added diethylamino-sulfurtrifluoride
(8 mL, 60 mmol) at 25.degree. C. and the mixture was stirred 16 h.
The reaction was quenched by addition of saturated aqueous
NaHCO.sub.3 dropwise at 0.degree. C. After separation of the two
phases, the organic phase was dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography over silica gel with 10% EtOAc in hexane to
yield 2-chloro-4-(1,1-difluoroethyl)pyridine (1.72 g) as a light
brown oil. GC/MS: m/z 177 [M.sup.+].
2-Chloro-4-(1,1-difluoroethyl)-pyridine 1-oxide
To a solution of 2-chloro-4-(1,1-difluoro)ethylpyridine (1.27 g, 7
mmol) in trifluoroacetic acid was added 30% hydrogen peroxide (6
mL) and the solution was heated at reflux 2.5 h. The reaction was
concentrated in vacuo and the residue poured into ice-cold water.
The mixture was neutralized with Na.sub.2CO.sub.3 and then
extracted with EtOAc and CH.sub.2Cl.sub.2. The pooled organic
layers were filtered and concentrated in vacuo to give
2-chloro-4-(1,1-difluoroethyl)-pyridine 1-oxide (1.00 g) as a brown
oil. .sup.1H NMR (CDCl.sub.3): .delta. 8.39 (d, J=6.6 Hz, 1H), 7.63
(d, J=2.4 Hz, 1H), 7.33 (dd, J=6.6, 2.4 Hz, 1H), 1.94 (t, J=18 Hz,
3H). GC/MS: m/z 193 [M.sup.+].
PREPARATION 10
##STR00043##
2-Fluoroisonicotinonitrile
Cesium fluoride (30 g, 0.22 mmol) was slurried in 150 mL dry
sulfolane and concentrated via vacuum distillation at 0.5 mm Hg.
After removal of 20% of the solvent, the suspension was cooled and
2-chloroisonicotinonitrile (15 g, 0.11 mmol) was added then stirred
and heated at 100.degree. C. for 20 h. It was cooled to 25.degree.
C., poured into 200 mL water and extracted with Et.sub.2O. The
ether phase was washed with water, then brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by column chromatography over silica gel with
CH.sub.2Cl.sub.2 to give 12.0 g of 2-fluoroisonicotinonitrile as a
low-melting colorless solid. MS m/z 122. .sup.1H NMR (CDCl.sub.3):
.delta. 8.45 (dd, 1H), 7.47 (dd, 1H), 7.24 (m, 1H).
1-(2-Fluoropyridin-4-yl)-ethanone
To a solution of 2-fluoroisonicotinonitrile (10 g, 82 mmol) in
anhydrous Et.sub.2O (250 mL) cooled in an ice-water bath was slowly
added 3M methyl magnesium bromide in hexane (40 mL, 120 mmol). The
mixture was stirred at 25.degree. C. overnight. The reaction was
quenched slowly with 1N aq. citric acid solution at 0.degree. C.
until all solids dissolved. Brine was added and the two phases were
separated. The organic phase was dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo to give
1-(2-fluoropyridin-4-yl)-ethanone (6.2 g) as a brown oil. The
aqueous phase was stirred at 25.degree. C. for 3 h, then extracted
with CH.sub.2Cl.sub.2. The dichloromethane layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give an
additional 1.1 g of the product, for a total of 7.3 g, used in the
next step without further purification. MS m/z 139. .sup.1H NMR
(CDCl.sub.3): .delta. 8.25 (dd, 1H), 7.47 (d, 1H), 7.21 (m,
1H).
2-Fluoro-4-(1,1-difluoroethyl)pyridine
1-(2-Fluoropyridin-4-yl)-ethanone (6.2 g, 44.6 mmol) from the
previous reaction was treated with diethylamino-sulfurtrifluoride
(17 mL, 130 mmol), as in Preparation 9, to yield 3.5 g of
2-fluoro-4-(1,1-difluoroethyl)pyridine (45% yield), as a light
yellow oil. GC/MS: m/z 161 [M.sup.+].
EXAMPLE 9
##STR00044##
(2-{4-[4-(1,1-Difluoroethyl)-6-methoxypyridin-2-yloxy]-phenyl}-ethyl)-(5,8-
-difluoroquinazolin-4-yl)-amine
To an ice-cold solution of
(2-{4-[4-(1,1-difluoroethyl)-1-oxypyridin-2-yloxy]phenyl}ethyl)-(5,8-difl-
uoroquinazolin-4-yl)amine (0.37 g, 0.85 mmol) and ethyl
chloroformate (0.22 g, 2.0 mmol) in MeOH (10 mL) was added
triethylamine (0.48 mL, 3.4 mmol) with stirring. The reaction
mixture was heated at reflux for 40 h. The solvent was removed
under reduced pressure, and the residue was then dissolved in
chloroform. The solution was washed with water, dried over
Na.sub.2SO.sub.4, filtered, concentrated, and the residue was
purified by column chromatography over silica gel with 10% EtOAc in
hexane to yield 0.128 g (33% yield) of the product as a pale brown
oil. .sup.1H NMR (CDCl.sub.3): .delta. 8.69 (s, 1H), 7.27-7.39 (m,
3H), 7.14 (d, J=8.4 Hz, 2H), 7.00 (m, 1H), 6.65-6.79 (br, 1H), 6.54
(s, 1H), 6.43 (s, 1H), 3.96 (q, J=6.9 Hz, 2H), 3.79 (s, 3H), 3.05
(t, J=6.9 Hz, 2H), 1.85 (t, J=18.3 Hz, 3H). LC/MS: 473.2
(M.sup.++1).
EXAMPLE 10
##STR00045##
{2-[4-(3-Chloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-difl-
uoroquinazolin-4-yl)-amine
{2-[4-(3,5-dichloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-
-difluoroquinazolin-4-yl)-amine (700 mg, 1.4 mol) was dissolved in
2B EtOH (100 mL) under nitrogen in a Parr shaker bottle.
Triethylamine (130 mg) and 10% Pd/C (200 mg) were added and the
bottle was charged with H.sub.2 to an initial pressure of 50 psi.
After shaking for approx. 10 min (approx 1 psi H.sub.2 uptake), the
reaction was filtered through Celite and concentrated in vacuo to
provide a white solid. The solid was partitioned between water and
EtOAc twice, and the pooled fractions were dried and concentrated
in vacuo. The residue was triturated with Et.sub.2O, to afford 310
mg of
{2-[4-(3-chloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-dif-
luoroquinazolin-4-yl)-amine as a white crystalline solid, M.P.
129-131.degree.. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.69 (s,
1 H), 8.35 (d, J=5.4 Hz, 1 H), 7.40-7.31 (m, 3 H), 7.12-7.06 (m, 2
H), 7.05-6.97 (m, 1 H), 6.85-6.66 (m, 2 H), 4.01-3.92 (m, 2 H),
3.09 (t, J=7.1 Hz, 2 H); MS: m/z 480.
EXAMPLE 11
##STR00046##
(5,8-Difluoroquinazolin-4-yl)-{2-[4-(2-trifluoromethylpyridin-4-yloxy)-phe-
nyl]-ethyl}-amine
To a suspension of 20% Pd(OH).sub.2 (500 mg) and sodium acetate
(368 mg, 4.5 mmol) and absolute EtOH (100 mL) under N.sub.2 in a
230 mL Corning shaker bottle was added
{2-[4-(3,5-dichloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-
-difluoroquinazolin-4-yl)-amine (1.15 g, 2.2 mmol). After
deaerating, the bottle was charged with H.sub.2 (57 psig initial
pressure) and shaken at room temp on Parr apparatus. After 24 h,
another aliquot of 20% Pd(OH).sub.2 was added, and the bottle was
recharged with H.sub.2. After another 24 h, the reaction mixture
was degassed, placed under nitrogen gas, and then filtered through
Celite. The filtrate was evaporated and the residue was purified
via preparative reverse phase LC (70% CH.sub.3CN/H.sub.2O, 0.5%
H.sub.3PO.sub.4 eluant) to provide 390 mg of
(5,8-difluoroquinazolin-4-yl)-{2-[4-(2-trifluoromethylpyridin-4-yloxy)-ph-
enyl]-ethyl}-amine as an off-white powder, M.P. 95-96.degree..
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.69 (s, 1 H), 8.56 (d,
J=5.7 Hz, 1 H), 7.40-7.31 (m, 3 H), 7.19 (d, J=2.4 Hz, 1 H),
7.10-7.05 (m, 2 H), 7.04-6.95 (m, 2 H), 6.73 (dt, J=16.6, 5.4 Hz, 1
H), 3.97 (q, J=6.9 Hz, 2 H), 3.09 (t, J=7.1 Hz, 1 H); MS: m/z
446.
PREPARATION 11
##STR00047##
{2-[4-(4-Trifluoromethylpyridin-3-yloxy)-phenyl]-ethyl}-carbamic
acid tert-butyl ester
To a solution of 3-fluoro-4-trifluoromethylpyridine (1 g, 6.1 mmol)
and [2-(4-hydroxyphenyl)-ethyl]-carbamic acid tert-butyl ester
(1.44 g, 6.1 mmol) in DMSO (10 mL) was added K.sub.2CO.sub.3 (5 g,
36.2 mmol), and the mixture was heated at 100.degree. C. for 30
min. After cooling, the solids were removed by suction filtration
and washed with Et.sub.2O. The pooled filtrates were diluted with
Et.sub.2O (75 mL) and washed with 0.01 N HCl. The organic layer was
concentrated in vacuo. The residue was dissolved in
Et.sub.2O/hexane and washed with 10% NaOH. The organic layer was
filtered and vacuum dried to provide 1.4 g (60% yield) of
{2-[4-(4-trifluoromethyl-pyridin-3-yloxy)-phenyl]-ethyl}-carbamic
acid tert-butyl ester as a clear, colorless oil.
2-[4-(1-Oxy-4-trifluoromethylpyridin-3-yloxy)-phenyl]-ethylamine
To a solution of
{2-[4-(4-trifluoromethylpyridin-3-yloxy)-phenyl]-ethyl}-carbamic
acid tert-butyl ester (0.87 g, 2.3 mmol) in DCM (40 mL) was added
pulverized commercial urea/hydrogen peroxide (0.45 g, 4.8 mmol) and
trifluoroacetic anhydride (1.2 g, 5.7 mmol). After 4 h, water (120
mL) was added. After 15 h, concentrated aqueous sodium bisulfite
solution was added to achieve a negative peroxide test. The
reaction mixture was extracted with Et.sub.2O and the pooled
organics were filtered and concentrated in vacuo to provide 0.89 g
of a semi-solid. This material was boiled in hexane, and the hexane
supernatant was decanted to leave 290 mg (43% yield) of
2-[4-(1-oxy-4-trifluoromethylpyridin-3-yloxy)-phenyl]-ethylamine as
a yellow gum, used without further purification in the next
step.
The hexane solution was concentrated in vacuo, and the residue was
dissolved in minimal diethyl ether, then diluted with 3 volumes of
pentane. Glassy crystals formed and were collected by suction
filtration to provide
{2-[4-(1-oxy-4-trifluoromethylpyridin-3-yloxy)-phenyl]-ethyl}-carbamic
acid tert-butyl ester as a crystalline solid (150 mg, 16% yield),
M.P. 97-99.degree.. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95
(d, J=6.4 Hz, 1 H), 7.76 (s, 1 H), 7.48 (d, J=6.8 Hz, 1 H),
7.29-7.23 (m, 2 H), 7.07-7.00 (m, 2 H), 4.60 (br, 1 H), 3.43-3.33
(m, 2H), 2.83 (t, J=7.0 Hz, 2 H), 1.45 (s, 9 H); MS m/z 398.
EXAMPLE 12
##STR00048##
(5,8-Difluoroquinazolin-4-yl)-{2-[4-(1-oxy-4-trifluoromethylpyridin-3-ylox-
y)-phenyl]-ethyl}-amine
A solution of
2-[4-(1-oxy-4-trifluoromethylpyridin-3-yloxy)-phenyl]-ethylamine
(0.23 g, 0.77 mmol) and
N'-(2-cyano-3,6-difluorophenyl)-N,N-dimethylformamidine (0.14 g) in
glacial acetic acid (6 mL) was heated on a steam bath for 24 h, and
then concentrated in vacuo. The residue was partitioned between
water (100 mL) and EtOAc. The organic layer was filtered and then
concentrated in vacuo to provide a brown gum. The gum was dissolved
in CH.sub.2Cl.sub.2, and precipitated by addition of hexane while
boiling off CH.sub.2Cl.sub.2. The supernatant was decanted to leave
0.16 g of
(5,8-difluoroquinazolin-4-yl)-{2-[4-(1-oxy-4-trifluoromethylpyridin-3-ylo-
xy)-phenyl]-ethyl}-amine as a tan solid, M.P. 165-170.degree.; MS
m/z 462; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.70 (s, 1 H),
7.97 (d, J=6.6 Hz, 1 H), 7.77 (s, 1 H), 7.49 (d, J=6.7 Hz, 1 H),
7.39-7.31 (m, 3 H), 7.12-7.06 (m, 2 H), 7.06-6.99 (m, 1 H),
6.78-6.67 (m, 1 H), 3.99-3.90 (m, 2 H), 3.08 (t, J=6.8 Hz, 2
H).
EXAMPLE 13
##STR00049##
(5,8-Difluoroquinazolin-4-yl)-{2-[4-(2-trifluoromethylpyrimidin-4-yloxy)-p-
henyl]-ethyl}-amine
A mixture of
{2-[4-(6-chloro-2-trifluoromethylpyrimidin-4-yloxy)-phenyl]-ethyl}-(5,8-d-
ifluoroquinazolin-4-yl)-amine (0.205 g, 0.46 mmol), 10% Pd on
activated carbon (0.030 g) and triethylamine (0.60 mL, 4.3 mmol) in
EtOH (15 mL) was charged with hydrogen to an initial pressure of 40
psi in a Parr bottle and shaken overnight. The catalyst was removed
by filtration on Celite and the filtrate was concentrated in vacuo.
The residue was purified on silica gel to give 0.087 g (42% yield)
of
(5,8-difluoroquinazolin-4-yl)-{2-[4-(2-trifluoromethylpyrimidin-4-yloxy)--
phenyl]-ethyl}-amine as a white foam, .sup.1H NMR (CDCl.sub.3):
.delta. 8.71 (d, J=6.3 Hz, 1H), 8.69 (s, 1H), 7.32-7.40 (m, 3H),
7.16 (d, J=8.7 Hz, 2H), 6.97-7.04 (m, 2H), 6.68-6.82 (br, 1H), 3.97
(q, J=6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H). LC/MS: 448.18
(M.sup.++1).
PREPARATION 12
##STR00050##
2-Amino-3,6-difluorobenzamide
2-Amino-3,6-difluorobenzonitrile (2.3 g, 15 mmol) was added to
concentrated sulfuric acid (5 mL) in a 25 mL 2-necked flask
equipped with a thermometer with good stirring. The temperature
rose to around 40.degree. C. and the mixture became homogeneous.
The solution was heated to 70.degree. C. for 2 hours, cooled to
room temperature, poured over ice, neutralized with concentrated
NH.sub.4OH using water and NH.sub.4OH to rinse the flask and adding
ice as necessary to keep the mixture cold. The separated solid was
collected by filtration, washed with water and dried to give
2-amino-3,6-difluorobenzamide, 2.2 g. A second crop of 0.24 g was
collected from the cold, concentrated filtrate, 95% overall. M.P.
121-123.degree. C., LC/MS (ESI) m/z 172, .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta. 7.70 (bs, 1H), 7.63 (bs, 1H), 7.10 (m, 1H),
6.32 (m, 1H), 6.05 (bs, 2H).
5,8-Difluoroquinazolin-4-ol
2-Amino-3,6-difluorobenzamide (2.0 g, 11.6 mmol), ammonium sulfate
(0.15 g, 1.16 mmol), triethylorthoformate (4.3 g, 4.8 mL, 29.1
mmol) and acetic anhydride (3.0 g, 2.8 mL, 29.1 mmol) were combined
in a 100 mL round bottomed flask and the mixture heated to
145.degree. C. on a heating mantle, becoming nearly homogeneous
around 90.degree. C., then precipitating additional solid. After 1
h, the mixture was cooled to room temperature and diluted with
water and stirred. The precipitated solids were collected by
filtration, washed with water and dried to give 1.95 g of
5,8-difluoroquinazolin-4-ol as a white solid. A second crop of 0.13
g was collected from the cold concentrated filtrate, 98% overall.
M.P. 257-258.degree. C., LC/MS (ESI) m/z 182, .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta. 12.48 (bs, 1H), 8.13 (s, 1H), 7.70 (m, 1H),
7.27 (m, 1H).
5,8-Difluoro-4-thiomethylquinazoline
5,8-Difluoroquinazolin-4-ol (0.215 g, 1.18 mmol) and Ph.sub.3P
(0.619 g, 2.36 mmol) were weighed into an oven-dried,
nitrogen-swept 100 mL round bottomed flask. Dichloroethane (5 mL)
and CCl.sub.4 (0.381 g, 2.48 mmol) were added via syringe and the
mixture was heated at reflux under nitrogen for 2 h, then cooled to
room temperature. Sodium methane thiolate (0.165 g, 2.36 mmol) was
added to the colorless, homogeneous solution and the resulting
mixture stirred briefly at room temperature. The crude reaction
mixture was transferred directly to a silica gel column (transfer
aided by a small volume rinse of the reaction flask with methylene
chloride) and purified by flash chromatography
(CH.sub.2Cl.sub.2:MeOH/20:1.fwdarw.10:1) to give 0.221 g (88%) as a
pale orange solid. M.P. 117-118.degree. C., LC/MS (ESI) m/z 212,
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.01 (s, 1H), 7.47 (m,
1H), 7.19 (m, 1H), 2.68 (s, 3H).
4-[2-(5,8-Difluoroquinazolin-4-ylamino)-ethyl]-phenol
5,8-Difluoro-4-thiomethylquinazoline (0.1 g, 0.47 mmol) and
tyramine (0.071 g, 0.52 mmol) were weighed into a 15 mL round
bottomed flask. CH.sub.3CN (2 mL) was added and the resulting
slurry heated to reflux under nitrogen to give a homogeneous
solution. After 2 days, the reaction was cooled, treated with an
additional tyramine (0.071 g, 0.52 mmol) and again heated to reflux
overnight. The reaction was cooled and diluted with water and the
resulting tan solid was collected by filtration and dried to give
0.11 g (77% yield) of
4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-phenol as a tan
solid.
PREPARATION 13
##STR00051##
4-Chloro-5,8-difluoroquinazoline
5,8-Difluoroquinazolin-4-ol (0.25 g, 1.4 mmol) was weighed into an
oven dried, nitrogen flushed 25 mL round bottomed flask. Thionyl
chloride (2 mL) was added along with DMF (2 drops) and the mixture
heated to reflux under nitrogen for 1 h giving a clear, yellow
homogeneous solution. After cooling to room temperature, the excess
SOCl.sub.2 was removed from the precipitated substrate in vacuo to
afford 4-chloro-5,8-difluoroquinazoline as a yellow solid, used
without further purification.
Biological Testing
The following Table I shows representative compounds of formula
(I), together with characterizing physical and biological data.
TABLE-US-00001 TABLE 1 Examples of compounds of formula (I)
including mass spectrometry results (MS; m/z), and biological
activity against representative fungal diseases and insects.
Activity Com- MS Activity against fungal diseases against pound
Structure m/z PSPECU PUCCRT PYRIOR SEPTTR insects 1 ##STR00052##
446 *** *** *** *** + 2 ##STR00053## 403 *** *** *** * + 3
##STR00054## 447 *** *** ** *** + 4 ##STR00055## 301 ** ** * * - 5
##STR00056## 464 *** *** *** ***b + 6 ##STR00057## 446 *** *** ***
*** + 7 ##STR00058## 460 *** *** *** *** + 8 ##STR00059## 462 ***
*** *** ** - 9 ##STR00060## 476 *** *** *** ** + 10 ##STR00061##
458 *** *** ** *** - 11 ##STR00062## 472 *** *** ** *** + 12
##STR00063## 442 *** *** *** *** + 13 ##STR00064## 446 NT ***a NR
***b + 14 ##STR00065## 331 ** * * *b - 15 ##STR00066## 476 *** ***
*** *** + 16 ##STR00067## 472 *** *** *** *** + 17 ##STR00068## 343
*** *** ** * + 18 ##STR00069## 329 * ** * * - 19 ##STR00070## 474
*** *** *** *** + 20 ##STR00071## 343 *** *** ** ** - 21
##STR00072## 329 *** ** ** *b - 22 ##STR00073## 488 NT *** ** ***b
+ 23 ##STR00074## 329 *** ** ** * - 24 ##STR00075## 315 * * * * -
25 ##STR00076## 460 *** *** *** *** + 26 ##STR00077## 474 *** ***
** *** + 27 ##STR00078## 319 * * * * - 28 ##STR00079## 504 *** ***
*** ***b + 29 ##STR00080## 490 *** *** ** *** + 30 ##STR00081## 504
** *** ** * - 31 ##STR00082## 464 *** *** *** *** + 32 ##STR00083##
394 *** *** ** * - 33 ##STR00084## 349 NT *a NT *b NT 34
##STR00085## 494 *** *** *** *** + 35 ##STR00086## 301 *** ** NT NT
- 36 ##STR00087## 518 *** *** NT *b + 37 ##STR00088## 460 *** ***
***a **b + 38 ##STR00089## 380 * * * NT - 39 ##STR00090## 525 ***
*** *** ***b + 40 ##STR00091## 446 *** *** *** **b + 41
##STR00092## 471 *** *** *** **b + 42 ##STR00093## 329 *** *** ***
*** + 43 ##STR00094## 446 *** *** ** *** + 44 ##STR00095## 490 ***
*** * *** + 45 ##STR00096## 494 *** *** * *** + 46 ##STR00097## 333
*** *** * * + 47 ##STR00098## 319 * * ** * - 48 ##STR00099## 482
*** *** *** *** + 49 ##STR00100## 464 *** *** *** *** + 50
##STR00101## 512 *** *** *** *** + 51 ##STR00102## 315 * * ** * -
52 ##STR00103## 460 *** *** *** *** + 53 ##STR00104## 512 *** ***
*** *** + 54 ##STR00105## 462 *** *** *** *** + 55 ##STR00106## 476
*** *** *** *** + 56 ##STR00107## 462 *** *** *** ** - 57
##STR00108## 504 *** *** *** *** + 58 ##STR00109## 504 *** *** ***
*** + 59 ##STR00110## 492 *** *** *** *** + 60 ##STR00111## 490 ***
*** *** *** + 61 ##STR00112## 476 *** *** ** *** - 62 ##STR00113##
351 NT NT NT NT NT 63 ##STR00114## 337 NT NT NT NT NT 64
##STR00115## 456 *** *** *** *** + 65 ##STR00116## 474 *** *** ***
*** + 66 ##STR00117## 472 *** *** *** *** + 67 ##STR00118## 482 ***
*** *** *** + 68 ##STR00119## 347 ** * *** * - 69 ##STR00120## 545
*** *** *** *** + 70 ##STR00121## 333 * ** ** ** - 71 ##STR00122##
446 NT ***a NT ***b NT 72 ##STR00123## 333 *** *** *** *b + 73
##STR00124## 319 NT NT NT NT NT 74 ##STR00125## 464 *** *** *** ***
+ 75 ##STR00126## 480 *** *** *** *** - 76 ##STR00127## 464 *** ***
*** *** + 77 ##STR00128## 476 *** *** *** *** + 78 ##STR00129## 510
*** *** *** *** NT 79 ##STR00130## 529 ** *** *** *** + 80
##STR00131## 478 *** *** *** *** + 81 ##STR00132## 494 *** *** ***
*** + 82 ##STR00133## 460 *** *** *** *** + 83 ##STR00134## 446 ***
*** *** *** + 84 ##STR00135## 462 *** *** *** *** + 85 ##STR00136##
349 *** * ** * - 86 ##STR00137## 367 *** * * * - 87 ##STR00138##
335 ** * * * - 88 ##STR00139## 353 *** * * * - 89 ##STR00140## 594
** *** ** ** + 90 ##STR00141## 480 *** *** *** *** + 91
##STR00142## 480 *** *** *** *** + 92 ##STR00143## 498 NT ** *** **
+ 93 ##STR00144## 498 NT *** *** *** + 94 ##STR00145## 285 *** ***
* ** + 95 ##STR00146## 515 *** *** *** *** - 96 ##STR00147## 480
*** *** *** *** + 97 ##STR00148## 447 *** *** *** ** + 98
##STR00149## 477 *** *** *** * + 99 ##STR00150## 461 *** *** *** *
+ 100 ##STR00151## 483 *** * * * - 101 ##STR00152## 513 *** ** * *
- 102 ##STR00153## 497 NT *** *** * - 103 ##STR00154## 481 NT ***
*** * - 104 ##STR00155## 511 NT *** *** * - 105 ##STR00156## 327 NT
*** *** * + 106 ##STR00157## 313 ** ** ** * - 107 ##STR00158## 412
*** *** *** ***b + 108 ##STR00159## 442 * *** * *** + 109
##STR00160## 447 NT *** *** *** + 110 ##STR00161## 458 *** *** ***
*** + 111 ##STR00162## 458 *** *** *** *** + 112 ##STR00163## 477
*** *** *** ***b + 113 ##STR00164## 477 *** *** *** ***b + 114
##STR00165## 447 *** *** *** **b + 115 ##STR00166## 462 *** *** ***
*** + 116 ##STR00167## 465 *** *** *** ***b + 117 ##STR00168## 461
*** *** *** ***b + 118 ##STR00169## 461 *** *** *** ***b + 119
##STR00170## 285 *** *** *** *** - 120 ##STR00171## 315 NT *** NT *
- 121 ##STR00172## 384 NT *a NT **b +
122 ##STR00173## 482 *** *** ** ***b + 123 ##STR00174## 446 NT ***a
NT ***b NT 124 ##STR00175## 429 *** *** *** **b + 125 ##STR00176##
437 *** *** *** *** + 126 ##STR00177## 437 *** *** *** ***b + 127
##STR00178## 413 *** *** *** * + 128 ##STR00179## 392 NT ***a NT
**b NT 129 ##STR00180## 437 *** *** *** ** - 130 ##STR00181## 464
*** *** *** *** + 131 ##STR00182## 482 *** *** *** *** + 132
##STR00183## 465 *** *** *** *** + 133 ##STR00184## 315 NT NT NT NT
NT 134 ##STR00185## 460 NT ***a NT ***b + 135 ##STR00186## 461 NT
***a NT ***b + 136 ##STR00187## 460 NT ***a NT ***b + 137
##STR00188## 478 NT **a NT ***b + 138 ##STR00189## 460 NT ***a NT
***b + 139 ##STR00190## 329 NT *a NT *b - 140 ##STR00191## 315 NT
NT NT NT - 141 ##STR00192## 460 NT ***a NT ***b + 142 ##STR00193##
461 NT ***a NT ***b + 143 ##STR00194## 460 NT *a NT ***b + 144
##STR00195## 460 NT ***a NT ***b + 145 ##STR00196## 478 NT *a NT
**b + a = Tested at 3 ppm b = Tested at 25 ppm NT = Not tested
Fungicide activity data are the level (in percent) at which the
given disease was controlled when the given compound was applied to
the foliage of the plants at 200 ppm. In a few cases (noted in the
table) the compound was applied to the plants at 25 ppm or 3 ppm.
The plants were inoculated with the fungus one day after treatment.
***=80-100% control; **=50-79% control; *=0-49% control.
Insect activity data; if any species was controlled at 80% or more,
the compound was considered active. "+" indicates activity; "-"
indicates lack of activity.
Fungicidal Activity
The compounds of the present invention have been found to have
significant fungicidal effect, particularly for agricultural use.
Many of the compounds are particularly effective for use with
agricultural crops and horticultural plants. In particular, the
compounds effectively control a variety of undesirable fungi that
infect useful plant crops. Activity has been demonstrated for a
variety of fungi, including for example the following
representative fungi species: Downy Mildew of Cucumber
(Pseudoperonospora cubensis--PSPECU), Rice Blast (Magnaporthe
grisea-PYRIOR), Brown Rust of Wheat (Puccinia recondita
tritici--PUCCRT); Septoria Blotch of Wheat (Septoria
tritici--SEPTTR).
It will be understood by those in the art that the efficacy of the
compounds against the foregoing fungi establishes the general
utility of the compounds as fungicides. The activity of the
compounds as effective fungicides was determined by applying the
compounds to plants and observing control of fungal disease. The
compounds were formulated at 200 ppm in 10 vol. % acetone plus 90
vol. % Triton X water (deionized water 99.99 wt %+0.01 wt % Triton
X100), giving a "formulated test compound." In a few cases,
compounds were formulated at 25 or 3 ppm rather than 200 ppm in 10
vol. % acetone plus 90 vol. % Triton X water (deionized water 99.99
wt. %+0.01 wt. % Triton X100), giving a "formulated test compound."
Formulated test compounds were applied to plants using a turn table
sprayer fitted with two opposing air atomization nozzles which
delivered approximately 1500 L/ha of spray volume.
All plants were inoculated with spores of the fungus the day after
treatment, then incubated in an environment conducive to disease
development. Disease severity was evaluated 4 to 25 days later,
depending on the speed of disease development. The following
experiments were performed in the laboratory to determine the
fungicidal efficacy of the compounds of the invention.
Leaf Rust of Wheat (causal agent Puccinia recondita
tritici=Puccinia triticina; Bayer code PUCCRT): Wheat plants
(variety `Yuma`) were grown from seed in a soil-less peat-based
potting mixture (Metromix) until the seedlings had a fully expanded
first leaf. Each pot contained 3-8 seedlings. These plants were
sprayed until wet with the formulated test compounds. On the
following day, the leaves were inoculated with an aqueous spore
suspension of Puccinia recondita tritici and the plants were kept
in high humidity overnight to permit spores to germinate and infect
the leaf. The plants were then transferred to a greenhouse until
disease developed on untreated control plants.
Cucumber Downy Mildew (causal agent Pseudoperonospora cubensis;
Bayer code PSPECU): Cucumber plants (variety "Bush Champion` or
`Bush Pickle Hybrid`) were grown from seed in a soil-less
peat-based potting mixture (Metromix) until the first true leaf was
20-80% expanded. Each pot contained 1 seedling. These plants were
sprayed until wet with the formulated test compound. On the
following day, the leaves were inoculated with an aqueous
suspension of downy mildew sporangia and the plants were kept in
high humidity for one day to permit sporangia to germinate and
infect the leaf. The plants were then incubated in a growth chamber
until disease developed on untreated control plants.
Rice Blast (causal agent Magnaporthe grisea=Pyricularia oryzae;
Bayer code PYRIOR): Rice plants (variety `M202`) were grown from
seed in a soil-less peat-based potting mixture (Metromix) until the
seedlings had a partly to fully expanded second leaf. Each pot
contained 5-20 seedlings. These plants were sprayed until wet with
the formulated test compound. On the following day, the leaves were
inoculated with an aqueous spore suspension of Pyricularia oryzae
and the plants were kept in high humidity overnight to permit
spores to germinate and infect the leaf. The plants were then
transferred to a growth chamber until disease developed on
untreated control plants.
Septoria Blotch of Wheat (causal agent Septoria tritici; Bayer code
SEPTTR): Wheat plants (variety `Yuma`) were grown from seed in a
50% pasteurized soil/50% soil-less mix until the seedlings had a
fully expanded first leaf. Each pot contained 3-10 seedlings. These
plants were sprayed until wet with the formulated test compound. On
the following day, the leaves were inoculated with an aqueous spore
suspension of Septoria tritici and the plants were kept in high
humidity (one day in a dark dew chamber followed by three days in a
lighted dew chamber) to permit spores to germinate and infect the
leaf. The plants were then transferred to a greenhouse until
disease developed on untreated control plants.
Table 1 presents the activity of typical compounds of the present
invention when evaluated in these experiments. The effectiveness of
the test compounds at controlling disease when sprayed on leaves
was determined by assessing the severity of disease on treated
plants, then converting the severity to percent control based on
the level of disease on untreated, inoculated plants.
Insecticidal Activity
The compounds of the present invention have been found to have
insecticidal activity. Activity may be demonstrated for a variety
of insects, including for example the following representative
insect species: Beet Armyworm (Spodoptera exigua--LAPHEG); Mosquito
(Aedes aegypti--AEDSAE), Fruit Fly (Drosophila
melanogaster--DROSME), and Colorado Potato Beetle (Leptinotarsa
decemlineata--LPTNDE). It will be understood by those in the art
that the efficacy of the compounds against the foregoing insects
establishes the general utility of the compounds as
insecticides.
The activity of the compounds as effective insecticides was
determined by applying the compounds to diet or water, placing
insects in the water or on the diet, and observing mortality after
an appropriate incubation time. The compounds were formulated at
4000 ppm in DMSO giving a "formulated test compound." Formulated
test compounds were diluted in 96-well plates with acetone:water
solutions and applied to species-specific diet or water. The plates
were infested and evaluated as described below. Results were
averaged over 2-6 replications. DROSME: Formulated test compounds
were applied to microtiter plates containing fruit fly agar (10%
sugar/water) to give a dose of 80 .mu.g test compound/well. Plates
were infested by placing at least three flies in each well and
sealing the plate. Mortality was evaluated after incubation for two
days at room temperature. AEDSAE: Plates containing formulated test
compounds at 6 .mu.g per well were diluted with water containing
mosquito larvae. Each well contained at least two larvae. Mortality
was evaluated after incubation for three days at room temperature.
LAPHEG: Formulated test compounds were applied to 96-well plates
containing Lepidoptera diet at 12 .mu.g per well. Plates were
infested by placing at least four fresh armyworm eggs in each well
and sealing the plate with cotton batting and plastic. Mortality
was evaluated after incubation for seven days at 28.degree. C.
LPTNDE: Formulated test compounds were diluted and sprayed onto
leaves of tomato plants. When dry, plant foliage was removed from
the plant and placed in 8-well agar trays. Five L2 Colorado potato
beetle larvae were placed in each well, and the trays were sealed
and incubated at 26.degree. C. Mortality was evaluated after three
days.
Table 1 presents the activity of typical compounds of the present
invention when evaluated in these experiments. The effectiveness of
the test compounds at controlling insects was determined by
assessing the mortality in treated test plates, then converting the
average mortality to percent control. If any of the three species
DROSME, AEDSAE, or LAPHEG was controlled at 80% or more, the
compound was considered active (shown as "+" in Table 1). If no
species was controlled at 80% or more, the compound was considered
inactive (shown as "-" in Table 1).
Synergy Activity
The compound was evaluated in mixtures with pyraclostrobin, or
epoxiconazole for protectant and curative activity against wheat
leaf rust (Puccinia triticina, PUCCRT), and Septoria blotch
(Septoria tritici, SEPTTR). Synergistic interactions were observed
for the tested fungicides against wheat leaf rust and Septoria
blotch in both curative and protectant evaluations in the
greenhouse.
The compound was formulated at six rates (8.1, 2.7, 0.9, 0.3, 0.1,
0.03 ppm) and applied to wheat plants alone and in all combinations
of it with pyraclostrobin or epoxiconazole using the methods
described in section "Fungicidal Activity" above. Plants were
inoculated three days before treatment (3DC) or one day after
treatment (1DP), incubated in a greenhouse until disease was
expressed, and visually rated (reported as % DC Obs) as described
above. The expected control was calculated using the Colby equation
(Colby, S. R. Calculation of the synergistic and antagonistic
response of herbicide combinations. Weeds 1967 15, 20-22.).
The following equation was used to calculate the expected activity
of mixtures containing two active ingredients, A and B:
Expected=A+B-(A.times.B/100)
A=observed efficacy of active ingredient A at the same
concentration as used in the mixture
B=observed efficacy of active ingredient B at the same
concentration as used in the mixture
Results are shown in Tables 2 and 3. In both protectant and
curative applications, the experimental compound had synergistic
activity with pyraclostrobin and epoxiconazole against both wheat
leaf rust and wheat leaf blotch.
TABLE-US-00002 TABLE 2 Synergistic control of Septoria blotch
(SEPTTR) by the compound and pyraclostrobin or epoxiconazole.
Expected disease control (% DC Exp) was calculated using the Colby
equation. Rate (ppm) % DC % DC Compound Compound Pyraclostrobin
Epoxiconazole Obs Exp 1DP SEPTTR 15 2.7 31 pyraclostrobin alone 0.3
49 epoxiconazole alone 0.3 36 15 + pyraclostrobin 2.7 0.3 93 65 15
+ epoxiconazole 2.7 0.3 93 56 3DC SEPTTR 15 0.9 22 pyraclostrobin
alone 0.1 14 epoxyconazole alone 0.3 35 15 + pyraclostrobin 0.9 0.1
69 34 15 + epoxiconazole 0.9 0.3 91 49
TABLE-US-00003 TABLE 3 Synergistic control of wheat leaf rust
(PUCCRT) by the experimental compound and pyraclostrobin or
epoxiconazole. Expected disease control (% DC Exp) was calculated
using the Colby equation. Rate (ppm) % DC % DC Compound Compound
Pyraclostrobin Epoxiconazole Obs Exp 1DP PUCCRT 15 0.3 33
pyraclostrobin alone 0.1 8 epoxiconazole alone 0.1 0 15 +
pyraclostrobin 0.3 0.1 73 39 15 + epoxiconazole 0.3 0.1 76 33 3DC
PUCCRT 15 0.9 52 15 0.3 6 pyraclostrobin alone 0.3 4 epoxiconazole
alone 0.1 13 15 + pyraclostrobin 0.9 0.3 83 54 15 + epoxiconazole
0.3 0.1 50 18
Animal Health Activity
The compounds of the present invention have been found to have
significant potential as anti-parasitics for animal health. Table
4, shown below, presents the activity of typical compounds of the
present invention when evaluated in these experiments. Activity has
been demonstrated by four out of six compounds screened against
Caenorhabditis elegans, a free-living nematode that is an indicator
species for animal parasites. It will be understood by those in the
art that the efficacy of four compounds against Caenorhabditis
elegans, which at 10 .mu.g/mL was equivalent to the commercial
anti-parasitic product ivermectin, establishes the potential
utility of these compounds to control parasites that attack
animals.
The activity of the compounds against Caenorhabditis elegans was
determined by dissolving compounds in DMSO, then applying them to
petri dishes containing Nematode Growth Medium agar to a final
concentration of 10 .mu.g compound per milliliter agar. Escherichia
coli bacteria were grown on the plates to provide a food source for
the larvae of Caenorhabditis elegans. The bacteria were heat-killed
at 65.degree. C. before compounds were added to the plates.
The plates with compound and heat-killed bacteria were infested
with 10 microliter drops containing eggs from wild-type
Caenorhabditis elegans worms. Adult worms were dissolved in KOH and
bleach and washed in Ringers solution to generate the egg
suspension. Each compound was screened with approximately 400 eggs,
divided between two petri dishes. Egg hatching was evaluated after
24 h at 20.degree. C. Mortality was averaged over the two
plates.
TABLE-US-00004 TABLE 4 Activity of compounds of the formula (I)
against Caenorhabditis elegans. Compound Percent mortality 3 100 42
6 76 100 93 100 115 100 125 0 Ivermectin 95 Untreated <2
Application rate is 10 micrograms per milliliter agar.
Other Activity
The effect on mice of oral exposure was determined for compounds
differing only in the number of fluorine substituents on the
quinazoline ring, as shown in Table 5. Three CD-1/Swiss derived
albino female mice were administered compounds by gavage as a 5%
w/v mixture in 0.5% carboxymethylcellulose solution. The animals
were monitored for 14 days.
TABLE-US-00005 TABLE 5 Effect of number of F substituents on
quinazoline ring on mice. Compounds in bold are shown in TABLE 1.
Number of F substituents Compound on quinazoline ring Mouse Oral
LD.sub.50 ##STR00197## 1 <100 mg/kg 6 2 100-500 mg/kg 31 3
>500 mg/kg
The effect of fluorine substitution was examined for additional
compound sets using an insect as a model, as shown in Table 6.
Colorado Potato Beetle (LPTNDE) sensitivity paralleled mouse
sensitivity and showed that the relationship of fluorine
substitution to animal sensitivity was general.
TABLE-US-00006 TABLE 6 Effect of number of F substituents on
quinazoline ring on Colorado Potato Beetle. Compounds in bold are
shown in TABLE 1. Number of F substituents Colorado Potato Beetle
Compound on quinazoline ring LC90 (ppm) ##STR00198## 1 31-12.5 6 2
12.5-50 31 3 50-200 ##STR00199## 1 0.12 1 2 0.49 74 3 1.0
##STR00200## 1 <3.1 124 2 3.1-12.5
* * * * *